Nucleic acid encoding human G protein-coupled receptor

ABSTRACT

The invention disclosed in this patent document relates to transmembrane receptors, more particularly to endogenous, human orphan G protein-coupled receptors. The invention provides, in part, polynucleotides encoding the endogenous, human orphan G protein-coupled receptors.

[0001] All references contained herein, whether to issued patents,patent applications, or non-patent references are hereby incorporated intheir entirety for any purpose.

FIELD OF THE INVENTION

[0002] The invention disclosed in this patent document relates totransmembrane receptors, and more particularly to endogenous, orphan,human G protein-coupled receptors (“GPCRs”).

BACKGROUND OF THE INVENTION

[0003] Although a number of receptor classes exist in humans, by far themost abundant and therapeutically relevant is represented by the Gprotein-coupled receptor (GPCR or GPCRs) class. It is estimated thatthere are some 100,000 genes within the human genome, and of these,approximately 2% or 2,000 genes, are estimated to code for GPCRs.Receptors, including GPCRs, for which the endogenous ligand has beenidentified are referred to as “known” receptors, while receptors forwhich the endogenous ligand has not been identified are referred to as“orphan” receptors. GPCRs represent an important area for thedevelopment of pharmaceutical products: from approximately 20 of the 100known GPCRs, 60% of all prescription pharmaceuticals have beendeveloped. This distinction is not merely semantic, particularly in thecase of GPCRs. Thus, the orphan GPCRs are to the pharmaceutical industrywhat gold was to California in the late 19^(th) century—an opportunityto drive growth, expansion, enhancement and development.

[0004] GPCRs share a common structural motif. All these receptors haveseven sequences of between 22 to 24 hydrophobic amino acids that formseven alpha helices, each of which spans the membrane (each span isidentified by number, i.e., transmembrane-1 (TM-1), transmebrane-2(TM-2), etc.). The transmembrane helices are joined by strands of aminoacids between transmembrane-2 and transmembrane-3, transmembrane-4 andtransmembrane-5, and transmembrane-6 and transmembrane-7 on theexterior, or “extracellular” side, of the cell membrane (these arereferred to as “extracellular” regions 1, 2 and 3 (EC-1, EC-2 and EC-3),respectively). The transmembrane helices are also joined by strands ofamino acids between transmembrane-1 and transmembrane-2, transmembrane-3and transmembrane-4, and transmembrane-5 and transmembrane-6 on theinterior, or “intracellular” side, of the cell membrane (these arereferred to as “intracellular” regions 1, 2 and 3 (IC-1, IC-2 and IC-3),respectively). The “carboxy” (“C”) terminus of the receptor lies in theintracellular space within the cell, and the “amino” (“N”) terminus ofthe receptor lies in the extracellular space outside of the cell.

[0005] Generally, when an endogenous ligand binds with the receptor(often referred to as “activation” of the receptor), there is a changein the conformation of the intracellular region that allows for couplingbetween the intracellular region and an intracellular “G-protein.” Ithas been reported that GPCRs are “promiscuous” with respect to Gproteins, i.e., that a GPCR can interact with more than one G protein.See, Kenakin, T., 43 Life Sciences 1095 (1988). Although other Gproteins exist, currently, Gq, Gs, Gi, and Go are G proteins that havebeen identified. Endogenous ligand-activated GPCR coupling with theG-protein begins a signaling cascade process (referred to as “signaltransduction”). Under normal conditions, signal transduction ultimatelyresults in cellular activation or cellular inhibition. It is thoughtthat the IC-3 loop as well as the carboxy terminus of the receptorinteract with the G protein.

[0006] Under physiological conditions, GPCRs exist in the cell membranein equilibrium between two different conformations: an “inactive” stateand an “active”state. A receptor in an inactive state is unable to linkto the intracellular signaling transduction pathway to produce abiological response. Changing the receptor conformation to the activestate allows linkage to the transduction pathway (via the G-protein) andproduces a biological response. A receptor may be stabilized in anactive state by an endogenous ligand or a compound such as a drug.

SUMMARY OF THE INVENTION

[0007] Disclosed herein are human endogenous orphan G protein-coupledreceptors.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008]FIGS. 1A and 1B provide reference “grids” for certain dot-blotsprovided herein (see also, FIG. 2A and 2B, respectively).

[0009]FIGS. 2A and 2B provide reproductions of the results of certaindot-blot analyses resulting from hCHN3 and hCHN8, respectively (seealso, FIGS. 1A and 1B, respectively).

[0010]FIG. 3 provides a reproduction of the results of RT-PCR analysisof hRUP3.

[0011]FIG. 4 provides a reproduction of the results of RT-PCR analysisof hRUP4.

[0012]FIG. 5 provides a reproduction of the results of RT-PCR analysisof hRUP6.

DETAILED DESCRIPTION

[0013] The scientific literature that has evolved around receptors hasadopted a number of terms to refer to ligands having various effects onreceptors. For clarity and consistency, the following definitions willbe used throughout this patent document. To the extent that thesedefinitions conflict with other definitions for these terms, thefollowing definitions shall control:

[0014] AMINO ACID ABBREVIATIONS used herein are set out in Table 1:TABLE 1 ALANINE ALA A ARGININE ARG R ASPARAGINE ASN N ASPARTIC ACID ASPD CYSTEINE CYS C GLUTAMIC ACID GLU E GLUTAMINE GLN Q GLYCINE GLY GHISTIDINE HIS H ISOLEUCINE ILE I LEUCINE LEU L LYSINE LYS K METHIONINEMET M PHENYLALANINE PHE F PROLINE PRO P SERINE SER S THREONINE THR TTRYPTOPHAN TRP W TYROSINE TYR Y VALINE VAL V

[0015] COMPOSITION means a material comprising at least one component.

[0016] ENDOGENOUS shall mean a material that a mammal naturallyproduces. ENDOGENOUS in reference to, for example and not limitation,the term “receptor,” shall mean that which is naturally produced by amammal (for example, and not limitation, a human) or a virus. Bycontrast, the term NON-ENDOGENOUS in this context shall mean that whichis not naturally produced by a mammal (for example, and not limitation,a human) or a virus.

[0017] HOST CELL shall mean a cell capable of having a Plasmid and/orVector incorporated therein. In the case of a prokaryotic Host Cell, aPlasmid is typically replicated as a autonomous molecule as the HostCell replicates (generally, the Plasmid is thereafter isolated forintroduction into a eukaryotic Host Cell); in the case of a eukaryoticHost Cell, a Plasmid is integrated into the cellular DNA of the HostCell such that when the eukaryotic Host Cell replicates, the Plasmidreplicates. Preferably, for the purposes of the invention disclosedherein, the Host Cell is eukaryotic, more preferably, mammalian, andmost preferably selected from the group consisting of 293, 293T andCOS-7 cells.

[0018] LIGAND shall mean an endogenous, naturally occurring moleculespecific for an endogenous, naturally occurring receptor.

[0019] NON-ORPHAN RECEPTOR shall mean an endogenous naturally occurringmolecule specific for an endogenous naturally occurring ligand whereinthe binding of a ligand to a receptor activates an intracellularsignaling pathway.

[0020] ORPHAN RECEPTOR shall mean an endogenous receptor for which theendogenous ligand specific for that receptor has not been identified oris not known.

[0021] PLASMID shall mean the combination of a Vector and cDNA.Generally, a Plasmid is introduced into a Host Cell for the purposes ofreplication and/or expression of the cDNA as a protein.

[0022] VECTOR sin reference to cDNA shall mean a circular DNA capable ofincorporating at least one cDNA and capable of incorporation into a HostCell.

[0023] The order of the following sections is set forth forpresentational efficiency and is not intended, nor should be construed,as a limitation on the disclosure or the claims to follow.

[0024] A. Identification of Human GPCRs

[0025] The efforts of the Human Genome project have led to theidentification of a plethora of information regarding nucleic acidsequences located within the human genome; it has been the case in thisendeavor that genetic sequence information has been made availablewithout an understanding or recognition as to whether or not anyparticular genomic sequence does or may contain open-reading frameinformation that translate human proteins. Several methods ofidentifying nucleic acid sequences within the human genome are withinthe purview of those having ordinary skill in the art. For example, andnot limitation, a variety of GPCRs, disclosed herein, were discovered byreviewing the GenBank™ database, while other GPCRs were discovered byutilizing a nucleic acid sequence of a GPCR, previously sequenced, toconduct a BLAST™ search of the EST database. Table A, below, lists thedisclosed endogenous orphan GPCRs along with a GPCR's respectivehomologous GPCR: TABLE A Open Reference To Disclosed Reading Per CentHomologous Human Accession Frame Homology To GPCR Orphan Number (BaseDesignated (Accession GPCRs Identified Pairs) GPCR No.) hARE-3 AL0333791,260 bp 52.3% LPA-R U92642 hARE-4 AC006087 1,119 bp 36% P2Y5 AF000546hARE-5 AC006255 1,104 bp 32% Oryzias D43633 latipes hGPR27 AA7758701,128 bp hARE-1 AI090920   999 bp 43% D13626 KIAA0001 hARE-2 AA3595041,122 bp 53% GPR27 hPPR1 H67224 1,053 bp 39% EBI1 L31581 hG2A AA7547021,113 bp 31% GPR4 L36148 hRUP3 AL035423 1,005 bp 30% 2133653 Drosophilamelanogaster hRUP4 AI307658 1,296 bp 32% pNPGPR NP_004876 28% and 29 %AAC41276 Zebra fish Ya and and Yb, AAB94616 respectively hRUP5 AC0058491,413 bp 25% DEZ Q99788 23% FMLPR P21462 hRUP6 AC005871 1,245 bp 48%GPR66 NP_006047 hRUP7 AC007922 1,173 bp 43% H3R AF140538 hCHN3 EST 365811,113 bp 53% GPR27 hCHN4 AA804531 1,077 bp 32% thrombin 4503637 hCHN6EST 2134670 1,503 bp 36% edg-1 NP_001391 hCHN8 EST 764455 1,029 bp 47%D13626 KIAA0001 hCHN9 EST 1541536 1,077 bp 41% LTB4R NM_000752 hCHN10EST 1365839 1,055 bp 35% P2Y NM_002563

[0026] Receptor homology is useful in terms of gaining an appreciationof a role of the disclosed receptors within the human body.Additionally, such homology can provide insight as to possibleendogenous ligand(s) that may be natural activators for the disclosedorphan GPCRs.

[0027] The ARE-2 receptor disclosed herein was discovered by screening ahuman genomic library using EST clone 68530 (GenBank Accession NumberAA359504). An analysis of this sequence by the named invnetor herein hasled to the discovery of a 1,122 base-pair open reading-frame, and uponanalysis thereof, this open reading-frame sequence evidences sequencehomology with the human GPR27, seven-transmembrane receptor.

[0028] The nucleic-acid sequence of the novel human receptor ARE-2 isset forth in SEQ.ID.NO.19 and the putative amino acid sequence thereofis set forth in SEQ.ID.NO.20. An alignment report comparing the sequenceset forth in SEQ.ID.NO.20 and the reported amino acid sequence for thehuman GPR27, seven-transmembrane receptor (see FIG. 1) indicates thereis a 53% sequence homology between these receptors.

[0029] B. Receptor Screening

[0030] Techniques have become more readily available over the past fewyears for endogenous-ligand identification (this, primarily, for thepurpose of providing a means of conducting receptor-binding assays thatrequire a receptor's endogenous ligand) because the traditional study ofreceptors has always proceeded from the a priori assumption(historically based) that the endogenous ligand must first be identifiedbefore discovery could proceed to find antagonists and other moleculesthat could affect the receptor. Even in cases where an antagonist mighthave been known first, the search immediately extended to looking forthe endogenous ligand. This mode of thinking has persisted in receptorresearch even after the discovery of constitutively activated receptors.What has not been heretofore recognized is that it is the active stateof the receptor that is most useful for discovering agonists, partialagonists, and inverse agonists of the receptor. For those diseases whichresult from an overly active receptor or an under-active receptor, whatis desired in a therapeutic drug is a compound which acts to diminishthe active state of a receptor or enhance the activity of the receptor,respectively, not necessarily a drug which is an antagonist to theendogenous ligand. This is because a compound that reduces or enhancesthe activity of the active receptor state need not bind at the same siteas the endogenous ligand. Thus, as taught by a method of this invention,any search for therapeutic compounds should start by screening compoundsagainst the ligand-independent active state.

[0031] As is known in the art, GPCRs can be “active” in their endogenousstate even without the binding of the receptor's endogenous ligandthereto. Such naturally-active receptors can be screened for the directidentification (i.e., without the need for the receptor's endogenousligand) of, in particular, inverse agonists. Alternatively, the receptorcan be “activated” via, e.g., mutation of the receptor to establish anon-endogenous version of the receptor that is active in the absence ofthe receptor's endogenous ligand.

[0032] Screening candidate compounds against an endogenous ornon-endogenous, constitutively activated version of the human orphanGPCRs disclosed herein can provide for the direct identification ofcandidate compounds which act at this cell surface receptor, withoutrequiring use of the receptor's endogenous ligand. By determining areaswithin the body where the endogenous version of human GPCRs disclosedherein is expressed and/or over-expressed, it is possible to determinerelated disease/disorder states which are associated with the expressionand/or over-expression of the receptor; such an approach is disclosed inthis patent document.

[0033] With respect to creation of a mutation that may evidenceconstitutive activation of human orphan GPCRs disclosed herein is basedupon the distance from the proline residue at which is presumed to belocated within TM6 of the GPCR typically nears the TM6/IC3 interface(such proline residue appears to be quite conserved). By mutating theamino acid residue located 16 amino acid residues from this residue(presumably located in the IC3 region of the receptor) to, mostpreferably, a lysine residue, such activation may be obtained. Otheramino acid residues may be useful in the mutation at this position toachieve this objective.

[0034] C. Disease/Disorder Identification and/or Selection

[0035] Preferably, the DNA sequence of the human orphan GPCR can be usedto make a probe for (a) dot-blot analysis against tissue-mRNA, and/or(b) RT-PCR identification of the expression of the receptor in tissuesamples. The presence of a receptor in a tissue source, or a diseasedtissue, or the presence of the receptor at elevated concentrations indiseased tissue compared to a normal tissue, can be preferably utilizedto identify a correlation with a treatment regimen, including but notlimited to, a disease associated with that disease. Receptors canequally well be localized to regions of organs by this technique. Basedon the known functions of the specific tissues to which the receptor islocalized, the putative functional role of the receptor can be deduced.

[0036] D. Screening of Candidate Compounds

[0037] 1. Generic GPCR Screening Assay Techniques

[0038] When a G protein receptor becomes constitutively active (i.e.,active in the absence of endogenous ligand binding thereto), it binds toa G protein (e.g., Gq, Gs, Gi, Go) and stimulates the binding of GTP tothe G protein. The G protein then acts as a GTPase and slowly hydrolyzesthe GTP to GDP, whereby the receptor, under normal conditions, becomesdeactivated. However, constitutively activated receptors continue toexchange GDP to GTP. A non-hydrolyzable analog of GTP, [³⁵S]GTPΓS, canbe used to monitor enhanced binding to membranes which expressconstitutively activated receptors. It is reported that [³⁵S]GTPΓS canbe used to monitor G protein coupling to membranes in the absence andpresence of ligand. An example of this monitoring, among other exampleswell-known and available to those in the art, was reported by Traynorand Nahorski in 1995. The preferred use of this assay system is forinitial screening of candidate compounds because the system isgenerically applicable to all G protein-coupled receptors regardless ofthe particular G protein that interacts with the intracellular domain ofthe receptor.

[0039] 2. Specific GPCR Screening Assay Techniques

[0040] Once candidate compounds are identified using the “generic” Gprotein-coupled receptor assay (i.e., an assay to select compounds thatare agonists, partial agonists, or inverse agonists), further screeningto confirm that the compounds have interacted at the receptor site ispreferred. For example, a compound identified by the “generic” assay maynot bind to the receptor, but may instead merely “uncouple” the Gprotein from the intracellular domain.

[0041] a. Gs and Gi.

[0042] Gs stimulates the enzyme adenylyl cyclase. Gi (and Go), on theother hand, inhibit this enzyme. Adenylyl cyclase catalyzes theconversion of ATP to cAMP; thus, constitutively activated GPCRs thatcouple the Gs protein are associated with increased cellular levels ofcAMP. On the other hand, constitutively activated GPCRs that couple theGi (or Go) protein are associated with decreased cellular levels ofcAMP. See, generally, “Indirect Mechanisms of Synaptic Transmission,”Chpt. 8, From Neuron To Brain (3^(rd) Ed.) Nichols, J. G. et al eds.Sinauer Associates, Inc. (1992). Thus, assays that detect cAMP can beutilized to determine if a candidate compound is, e.g., an inverseagonist to the receptor (i.e., such a compound would decrease the levelsof cAMP). A variety of approaches known in the art for measuring cAMPcan be utilized; a most preferred approach relies upon the use ofanti-cAMP antibodies in an ELISA-based format. Another type of assaythat can be utilized is a whole cell second messenger reporter systemassay. Promoters on genes drive the expression of the proteins that aparticular gene encodes. Cyclic AMP drives gene expression by promotingthe binding of a cAMP-responsive DNA binding protein or transcriptionfactor (CREB) which then binds to the promoter at specific sites calledcAMP response elements and drives the expression of the gene. Reportersystems can be constructed which have a promoter containing multiplecAMP response elements before the reporter gene, e.g., β-galactosidaseor luciferase. Thus, a constitutively activated Gs-linked receptorcauses the accumulation of cAMP that then activates the gene andexpression of the reporter protein. The reporter protein such asβ-galactosidase or luciferase can then be detected using standardbiochemical assays (Chen et al. 1995).

[0043] b. Go and Gq.

[0044] Gq and Go are associated with activation of the enzymephospholipase C, which in turn hydrolyzes the phospholipid PIP₂,releasing two intracellular messengers: diacycloglycerol (DAG) andinistol 1,4,5-triphoisphate (IP₃). Increased accumulation of IP₃ isassociated with activation of Gq- and Go-associated receptors. See,generally, “Indirect Mechanisms of Synaptic Transmission,” Chpt. 8, FromNeuron To Brain (3^(rd) Ed.) Nichols, J. G. et al eds. SinauerAssociates, Inc. (1992). Assays that detect IP₃ accumulation can beutilized to determine if a candidate compound is, e.g., an inverseagonist to a Gq- or Go-associated receptor (i.e., such a compound woulddecrease the levels of IP₃). Gq-associated receptors can also beenexamined using an AP1 reporter assay in that Gq-dependent phospholipaseC causes activation of genes containing AP1 elements; thus, activatedGq-associated receptors will evidence an increase in the expression ofsuch genes, whereby inverse agonists thereto will evidence a decrease insuch expression, and agonists will evidence an increase in suchexpression. Commercially available assays for such detection areavailable.

[0045] 3. GPCR Fusion Protein

[0046] The use of an endogenous, constitutively activated orphan GPCR,or a non-endogenous, constitutively activated orphan GPCR, for screeningof candidate compounds for the direct identification of inverseagonists, agonists and partial agonists provides a unique challenge inthat, by definition, the receptor is active even in the absence of anendogenous ligand bound thereto. Thus, it is often useful that anapproach be utilized that can enhance the signal obtained by theactivated receptor. A preferred approach is the use of a GPCR FusionProtein.

[0047] Generally, once it is determined that a GPCR is or has beenconstitutively activated, using the assay techniques set forth above (aswell as others), it is possible to determine the predominant G proteinthat couples with the endogenous GPCR. Coupling of the G protein to theGPCR provides a signaling pathway that can be assessed. Because it ismost preferred that screening take place by use of a mammalianexpression system, such a system will be expected to have endogenous Gprotein therein. Thus, by definition, in such a system, theconstitutively activated orphan GPCR will continuously signal. In thisregard, it is preferred that this signal be enhanced such that in thepresence of, e.g., an inverse agonist to the receptor, it is more likelythat it will be able to more readily differentiate, particularly in thecontext of screening, between the receptor when it is contacted with theinverse agonist.

[0048] The GPCR Fusion Protein is intended to enhance the efficacy of Gprotein coupling with the GPCR. The GPCR Fusion Protein is preferred forscreening with a non-endogenous, constitutively activated GPCR becausesuch an approach increases the signal that is most preferably utilizedin such screening techniques, although the GPCR Fusion Protein can alsobe (and preferably is) used with an endogenous, constitutively activatedGPCR. This is important in facilitating a significant “signal to noise”ratio; such a significant ratio is import preferred for the screening ofcandidate compounds as disclosed herein.

[0049] The construction of a construct useful for expression of a GPCRFusion Protein is within the purview of those having ordinary skill inthe art. Commercially available expression vectors and systems offer avariety of approaches that can fit the particular needs of aninvestigator. The criteria of importance for such a GPCR Fusion Proteinconstruct is that the GPCR sequence and the G protein sequence both bein-frame (preferably, the sequence for the GPCR is upstream of the Gprotein sequence) and that the “stop” codon of the GPCR must be deletedor replaced such that upon expression of the GPCR, the G protein canalso be expressed. The GPCR can be linked directly to the G protein, orthere can be spacer residues between the two (preferably, no more thanabout 12, although this number can be readily ascertained by one ofordinary skill in the art). We have a preference (based uponconvenience) of use of a spacer in that some restriction sites that arenot used will, effectively, upon expression, become a spacer. Mostpreferably, the G protein that couples to the GPCR will have beenidentified prior to the creation of the GPCR Fusion Protein construct.Because there are only a few G proteins that have been identified, it ispreferred that a construct comprising the sequence of the G protein(i.e., a universal G protein construct) be available for insertion of anendogenous GPCR sequence therein; this provides for efficiency in thecontext of large-scale screening of a variety of different endogenousGPCRs having different sequences.

[0050] E. Other Utility

[0051] Although a preferred use of the human orphan GPCRs disclosedherein may be for the direct identification of candidate compounds asinverse agonists, agonists or partial agonists (preferably for use aspharmaceutical agents), these versions of human GPCRs can also beutilized in research settings. For example, in vitro and in vivo systemsincorporating GPCRs can be utilized to further elucidate and understandthe roles these receptors play in the human condition, both normal anddiseased, as well as understanding the role of constitutive activationas it applies to understanding the signaling cascade. The value in humanorphan GPCRs is that its utility as a research tool is enhanced in thatby determining the location(s) of such receptors within the body, theGPCRs can be used to understand the role of these receptors in the humanbody before the endogenous ligand therefor is identified. Other uses ofthe disclosed receptors will become apparent to those in the art basedupon, inter alia, a review of this patent document.

EXAMPLES

[0052] The following examples are presented for purposes of elucidation,and not limitation, of the present invention. While specific nucleicacid and amino acid sequences are disclosed herein, those of ordinaryskill in the art are credited with the ability to make minormodifications to these sequences while achieving the same orsubstantially similar results reported below. Unless otherwise indicatedbelow, all nucleic acid sequences for the disclosed endogenous orphanhuman GPCRs have been sequenced and verified. For purposes of equivalentreceptors, those of ordinary skill in the art will readily appreciatethat conservative substitutions can be made to the disclosed sequencesto obtain a functionally equivalent receptor.

Example 1 Endogenous Human GPCRs

[0053] 1. Identification of Human GPCRs

[0054] Several of the disclosed endogenous human GPCRs were identifiedbased upon a review of the GenBank database information. While searchingthe database, the following cDNA clones were identified as evidencedbelow. Disclosed Human Complete DNA Open Reading Nucleic Acid OrphanAccession Sequence Frame SEQ. ID. Amino Acid GPCRs Number (Base Pairs)(Base Pairs) NO. SEQ. ID. NO. hARE-3 AL033379 111,389 bp 1,260 bp 1 2hARE-4 AC006087 226,925 bp 1,119 bp 3 4 hARE-5 AC006255 127,605 bp 1,104bp 5 6 hRUP3 AL035423 140,094 bp 1,005 bp 7 8 hRUP5 AC005849 169,144 bp1,413 bp 9 10 hRUP6 AC005871 218,807 bp 1,245 bp 11 12 hRUP7 AC007922158,858 bp 1,173 bp 13 14

[0055] Other disclosed endogenous human GPCRs were identified byconducting a BLAST search of EST database (dbest) using the followingEST clones as query sequences. The following EST clones identified werethen used as a probe to screen a human genomic library. Disclosed OpenHuman EST Clone/ Reading Orphan Query Accession No. Frame Nucleic AcidAmino Acid GPCRs (Sequence) Identified (Base Pairs) SEQ. ID. NO. SEQ.ID. NO. hGPCR27 Mouse AA775870 1,125 bp 15 16 GPCR27 hARE-1 TDAG 1689643  999 bp 17 18 AI090920 hARE-2 GPCR27 68530 1,122 bp 19 20 AA359504hPPR1 Bovine 238667 1,053 bp 21 22 PPR1 H67224 hG2A Mouse See Example2(a), 1,113 bp 23 24 1179426 below hCHN3 N.A. EST 36581 1,113 bp 25 26(full length) hCHN4 TDAG 1184934 1,077 bp 27 28 AA804531 hCHN6 N.A. EST2134670 1,503 bp 29 30 (full length) hCHN8 KIAA0001 EST 764455 1,029 bp31 32 hCHN9 1365839 EST 1541536 1,077 bp 33 34 hCHN10 Mouse EST Human1365839 1,005 bp 35 36 1365839 hRUP4 N.A. AI307658 1,296 bp 37 38

[0056] 1.a Identification of Human ARE-2

[0057] The disclosed human ARE-2 was identified based upon the use ofEST database information. The nucleic acid sequence of human GPR27 wasused to conduct a BLAST search of the EST database (“dbest” search). ESTclone 68530 (Genbank Accession Number AA359504) was identified from thissearch and then used as a probe to screen a human genomic library(Stratagene, #942503), following manufacturer instructions. Thisresulted in a positive genomic clone; the fragment containing a codingsequence was localized with restriction mapping and Southern blotanalysis. This fragment was then subcloned into pBluScript (Stratagene),followed by sequencing (SEQ.ID.NO.:1) of human ARE-2. This sequence wasthen-sub-cloned into pCMV (see infra). The putative amino acid sequencefor ARE-2 is set forth in SEQ.ID.NO.:2.

[0058] 1.b Preparation of Non-Endogenous, Constitutively Activated ARE-2

[0059] Preparation of the non-endogenous human ARE-2 receptor that mayevidence constitutive activation of the receptor disclosed herein may beaccomplished by creating a mutation at position 285G, most preferably anG285K mutation. Mutagenesis can preferably be performed using aTransformer Site-Directed™ Mutagenesis Kit (Clontech) according tomanufacturer's instructions. The two mutagenesis primers are to beutilized, a lysine mutagenesis oligonucleotide that creates the lysinemutation at amino acid position 285G (e.g., changing GGC to AAA atnucelotides 853-855) and a selection marker oligonucleotide.

[0060] 2. Full Length Cloning

[0061] a. hG2A (Seq. Id. Nos. 23 & 24) Mouse EST clone 1179426 was usedto obtain a human genomic clone containing all but three amino acid hG2Acoding sequences. The 5′end of this coding sequence was obtained byusing 5′RACE™, and the template for PCR was Clontech's Human SpleenMarathon-ready™ cDNA. The disclosed human G2A was amplified by PCR usingthe G2A cDNA specific primers for the first and second round PCR asshown in SEQ.ID.NO.:39 and SEQ.ID.NO.:40 as follows:5′-CTGTGTACAGCAGTTCGCAGAGTG-3′ (SEQ. ID. NO.: 39; 1^(st) round PCR)5′-GAGTGCCAGGCAGAGCAGGTAGAC-3′. (SEQ. ID. NO.: 40; second round PCR)

[0062] PCR was performed using Advantage™ GC Polymerase Kit (Clontech;manufacturing instructions will be followed), at 94° C. for 30 secfollowed by 5 cycles of 94° C. for 5 sec and 72° C. for 4 min; and 30cycles of 94° for 5 sec and 70° for 4 min. An approximate 1.3 Kb PCRfragment was purified from agarose gel, digested with Hind III and Xba Iand cloned into the expression vector pRC/CMV2 (Invitrogen). Thecloned-insert was sequenced using the T7 Sequenase™ kit (USB Amersham;manufacturer instructions will be followed) and the sequence wascompared with the presented sequence. Expression of the human G2A willbe detected by probing an RNA dot blot (Clontech; manufacturerinstructions will be followed) with the P³²-labeled fragment.

[0063] b. hCHN9 (Seq. Id. Nos. 33 & 34)

[0064] Sequencing of the EST clone 1541536 indicated that hCHN9 is apartial cDNA clone having only an initiation codon; i.e., thetermination codon was missing. When hCHN9 was used to “blast” againstthe data base (nr), the 3′ sequence of hCHN9 was 100% homologous to the5′ untranslated region of the leukotriene B4 receptor cDNA, whichcontained a termination codon in the frame with hCHN9 coding sequence.To determine whether the 5′ untranslated region of LTB4R cDNA was the 3′sequence of hCHN9, PCR was performed using primers based upon the 5′sequence flanking the initiation codon found in hCHN9 and the 3′sequence around the termination codon found in the LTB4R 5′ untranslatedregion. The 5′ primer sequence utilized was as follows:5′-CCCGAATTCCTGCTTGCTCCCAGCTTGGCCC-3′ (SEQ. ID. NO.: 41; sense) and5′-TGTGGATCCTGCTGTCAAAGGTCCCATTCCGG-3′. (SEQ. ID. NO.: 42; antisense)

[0065] PCR was performed using thymus cDNA as a template and rTthpolymerase (Perkin Elmer) with the buffer system provided by themanufacturer, 0.25 uM of each primer, and 0.2 mM of each 4 nucleotides.The cycle condition was 30 cycles of 94° C. for 1 min, 65° C. for minand 72° C. for 1 min and 10 sec. A 1.1 kb fragment consistent with thepredicted size was obtained from PCR. This PCR fragment was subclonedinto pCMV (see below) and sequenced (see, SEQ.ID.NO.:33).

[0066] c. hRUP 4 (Seq. Id. Nos. 37 & 38)

[0067] The full length hRUP4 was cloned by RT-PCR with human brain cDNA(Clontech) as templates: 5′-TCACAATGCTAGGTGTGGTC-3′ (SEQ. ID. NO.: 43;and sense) 5′-TGCATAGACAATGGGATTACAG-3′. (SEQ. ID. NO.: 44; antisense)

[0068] PCR was performed using TaqPlus™ Precision™ polymerase(Stratagene; manufacturing instructions will be followed) by thefollowing cycles: 94° C. for 2 min; 94° C. 30 sec; 55° C. for 30 sec,72° C. for 45 sec, and 72° C. for 10 min. Cycles 2 through 4 wererepeated 30 times.

[0069] The PCR products were separated on a 1% agarose gel and a 500 bpPCR fragment was isolated and cloned into the pCRII-TOPO vector(Invitrogen) and sequenced using the T7 DNA Sequenase™ kit (Amsham) andthe SP6/T7 primers (Stratagene). Sequence analysis revealed that the PCRfragment was indeed an alternatively spliced form of AI307658 having acontinuous open reading frame with similarity to other GPCRs. Thecompleted sequence of this PCR fragment was as follows:5′-TCACAATGCTAGGTGTGGTCTGGCTGGTG (SEQ. ID. NO.: 45)GCAGTCATCGTAGGATCACCCATGTGGCACGT GCAACAACTTGAGATCAAATATGACTTCCTATATGAAAAGGAACACATCTGCTGCTTAGAAGAG TGGACCAGCCCTGTGCACCAGAAGATCTACACCACCTTCATCCTTGTCATCCTCTTCCTCCTGC CTCTTATGGTGATGCTTATTCTGTACGTAAAATTGGTTATGAACTTTGGATAAAGAAAAGAGTT GGGGATGGTTCAGTGCTTCGAACTATTCATGGAAAAGAAATGTCCAAAATAGCCAGGAAGAAGA AACGAGCTGTCATTATGATGGTGACAGTGGTGGCTCTCTTTGCTGTGTGCTGGGCACCATTCCA TGTTGTCCATATGATGATTGAATACAGTAATTTTGAAAAGGAATATGATGATGTCACAATCAAG ATGATTTTTGCTATCGTGCAAATTATTGGATTTTCCAACTCCATCTGTAATCCCATTGTCTATG CA-3′

[0070] Based on the above sequence, two sense oligonucleotide primersets: 5′-CTGCTTAGAAGAGTGGACCAG-3′, (SEQ. ID. NO.: 46; oligo 1)5′-CTGTGCACCAGAAGATCTACAC-3′ (SEQ. IDNO.: 47; oligo 2)

[0071] and two antisense oligonucleotide primer sets:5′-CAAGGATGAAGGTGGTGTAGA-3′ (SEQ. ID. NO.: 48; oligo 3)5′-GTGTAGATGTTCTGGTGCACAGG-3′ (SEQ. ID. NO.: 49; oligo 4)

[0072] were used for 3′- and 5′-race PCR with a human brainMarathon-Ready™ cDNA (Clontech, Cat# 7400-1) as template, according tomanufacture's instructions. DNA fragments generated by the RACE PCR werecloned into the pCRII-TOPO™ vector (Invitrogen) and sequenced using theSP6/T7 primers (Stratagene) and some internal primers. The 3′ RACEproduct contained a poly(A) tail and a completed open reading frameending at a TAA stop codon. The 5′ RACE product contained an incomplete5′ end; i.e., the ATG initiation codon was not present.

[0073] Based on the new 5′ sequence, oligo 3 and the following primer:

[0074] 5′-GCAATGCAGGTCATAGTGAGC -3′ (SEQ.ID.NO.: 50; oligo 5)

[0075] were used for the second round of 5′ RACE PCR and the PCRproducts were analyzed as above. A third round of 5′ RACE PCR wascarried out utilizing antisense primers:5′-TGGAGCATGGTGACGGGAATGCAGAAG-3′ and (SEQ. ID. NO.: 51; oligo 6)5′-GTGATGAGCAGGTCACTGAGCGCCAAG-3′. (SEQ. ID. NO.: 52; oligo 7)

[0076] The sequence of the 5′ RACE PCR products revealed the presence ofthe initiation codon ATG, and further round of 5′ RACE PCR did notgenerate any more 5′ sequence. The completed 5′ sequence was confirmedby RT-PCR using sense primer

[0077] 5′-GCAATGCAGGCGCTTAACATTAC-3′ (SEQ.ID.NO.: 53; oligo 8)

[0078] and oligo 4 as primers and sequence analysis of the 650 bp PCRproduct generated from human brain and heart cDNA templates (Clontech,Cat# 7404-1). The completed 3′ sequence was confirmed by RT-PCR usingoligo 2 and the following antisense primer:

[0079] 5′-TTGGGTTACAATCTGAAGGGCA-3′ (SEQ.ID.NO.: 54; oligo 9)

[0080] and sequence analysis of the 670 bp PCR product generated fromhuman brain and heart cDNA templates. (Clontech, Cat# 7404-1).

[0081] d. hRUP5 (Seq. Id. Nos. 9 & 10)

[0082] The full length hRUP5 was cloned by RT-PCR using a sense primerupstream from ATG, the initiation codon (SEQ.ID.NO.: 55), and anantisense primer containing TCA as the stop codon (SEQ.ID.NO.: 56),which had the following sequences: 5′-ACTCCGTGTCCAGCAGGACTCTG-3′ (SEQ.ID. NO. :55) 5′-TGCGTGTTCCTGGACCCTCACGTG-3′ (SEQ. ID. NO.: 56)

[0083] and human peripheral leukocyte cDNA (Clontech) as a template.Advantage cDNA polymerase (Clontech) was used for the amplification in a50 ul reaction by the following cycle with step 2 through step 4repeated 30 times: 94° C. for 30 sec; 94° for 15 sec; 69° for 40 sec;72° C. for 3 min; and 72° C. fro 6 min. A 1.4 kb PCR fragment wasisolated and cloned with the pCRII-TOPO™ vector (Invitrogen) andcompletely sequenced using the T7 DNA Sequenase™ kit (Amsham). See,SEQ.ID.NO.: 9.

[0084] e. hRUP6 (Seq. Id. Nos. 11 & 12)

[0085] The full length hRUP6 was cloned by RT-PCR using primers:5′-CAGGCCTTGGATTTTAATGTCAGGGATGG-3′ and (SEQ. ID. NO.: 57)5′-GGAGAGTCAGCTCTGAAAGAATTCAGG-3′; (SEQ. ID. NO.: 58)

[0086] and human thymus Marathon-Ready™ cDNA (Clontech) as a template.Advantage cDNA polymerase (Clontech, according to manufacturer'sinstructions) was used for the amplification in a 50 ul reaction by thefollowing cycle: 94° C. for 30 sec; 94° C. for 5 sec; 66° C. for 40 sec;72° C. for 2.5 sec and 72° C. for 7 min. Cycles 2 through 4 wererepeated 30 times. A 1.3 Kb PCR fragment was isolated and cloned intothe pCRII-TOPO™ vector (Invitrogen) and completely sequenced (see,SEQ.ID.NO.: 11) using the ABI Big Dye Terminator™ kit (P.E. Biosystem).

[0087] f. hRUP7 (Seq. Id. Nos. 13 & 14)

[0088] The full length RUP7 was cloned by RT-PCR using primers:5′-TGATGTGATGCCAGATACTAATAGCAC-3′ (SEQ. ID. NO.: and 59; sense)5′-CCTGATTCATTTAGGTGAGATTGAGAC-3′ (SEQ. ID. NO.: 60; antisense)

[0089] and human peripheral leukocyte cDNA (Clontech) as a template.Advantage™ cDNA polymerase (Clontech) was used for the amplification ina 50 ul reaction by the following cycle with step 2 to step 4 repeated30 times: 94° C. for 2 minutes; 94° C. for 15 seconds; 60° C. for 20seconds; 72° C. for 2 minutes; 72° C. for 10 minutes. A 1.25 Kb PCRfragment was isolated and cloned into the pCRII-TOPO™ vector(Invitrogen) and completely sequenced using the ABI Big Dye Terminator™kit (P.E. Biosystem). See, SEQ.ID.NO.: 13.

[0090] g. hARE-5 (Seq. Id. Nos. 5 & 6)

[0091] The full length hARE-5 was cloned by PCR using the hARE5 specificprimers 5′-CAGCGCAGGGTGAAGCCTGAGAGC-3′ SEQ.ID.NO.: 69 (sense, 5′ ofinitiation codon ATG) and 5′-GGCACCTGCTGTGACCTGTGCAGG-3′ SEQ.ID.NO.:70(antisense, 3′ of stop codon TGA) and human genomic DNA as template.TaqPlus Precision™ DNA polymerase (Stratagene) was used for theamplification by the following cycle with step 2 to step 4 repeated 35times: 96° C., 2 minutes; 96° C., 20 seconds; 58° C., 30 seconds; 72°C., 2 minutes; and 72° C., 10 minutes

[0092] A 1.1 Kb PCR fragment of predicated size was isolated and clonedinto the pCRII-TOPO™ vector (Invitrogen) and completely sequenced(SEQ.ID.NO.:5) using the T7 DNA Sequenase™ kit (Amsham).

[0093] h. hARE-4 (Seq. Id. Nos.: 3 & 4)

[0094] The full length hARE-4 was cloned by PCR using the hARE-4specific primers 5′-CTGGTGTGCTCCATGGCATCCC-3′ SEQ.ID.NO.:67 (sense, 5′of initiation codon ATG) and 5′-GTAAGCCTCCCAGAACGAGAGG-3′ SEQ.ID.NO.: 68(antisense, 3′ of stop codon TGA) and human genomic DNA as template. TaqDNA polymerase (Stratagene) and 5% DMSO was used for the amplificationby the following cycle with step 2 to step 3 repeated 35 times: 94° C.,3 minutes; 94° C., 30 seconds; 59° C., 2 minutes; 72° C., 10 minutes

[0095] A 1.12 Kb PCR fragment of predicated size was isolated and clonedinto the pCRII-TOPO™ vector (Invitrogen) and completely sequenced(SEQ.ID.NO.:3) using the T7 DNA Sequenase™ kit (Amsham).

[0096] i. hARE-3 (Seq.Id.Nos.: 1 & 2)

[0097] The full length hARE-3 was cloned by PCR using the hARE-3specific primers 5′-gatcaagcttCCATCCTACTGAAACCATGGTC-3′ SEQ.ID.NO.:65(sense, lower case nucleotides represent Hind III overhang, ATG asinitiation codon) and 5′-gatcagatctCAGTTCCAATATTCACACCACCGTC-3′SEQ.ID.NO.:66 (antisense, lower case nucleotides represent Xba Ioverhang, TCA as stop codon) and human genomic DNA as template. TaqPlusPrecision™ DNA polymerase (Stratagene) was used for the amplification bythe following cycle with step 2 to step 4 repeated 35 times: 94° C., 3minutes; 94° C., 1 minute; 55° C., 1 minute; 72° C., 2 minutes; 72° C.,10 minutes.

[0098] A 1.3 Kb PCR fragment of predicated size was isolated anddigested with Hind III and Xba I, cloned into the pRC/CMV2 vector(Invitrogen) at the Hind III and Xba I sites and completely sequenced(SEQ.ID.NO.:1) using the T7 DNA Sequenase™ kit (Amsham).

[0099] j. hRUP3 (Seq. Id. Nos.:7 & 8)

[0100] The full length hRUP3 was cloned by PCR using the hRUP3 specificprimers 5′-GTCCTGCCACTTCGAGACATGG-3′ SEQ.ID.NO.:71 (sense, ATG asinitiation codon) and 5′-GAAACTTCTCTGCCCTTACCGTC-3′ SEQ.ID.NO.:72(antisense, 3′ of stop codon TAA) and human genomic DNA as template.TaqPlus Precision™ DNA polymerase (Stratagene) was used for theamplification by the following cycle with step 2 to step 4 repeated 35times: 94° C., 3 minutes; 94° C., 1 minute; 58° C., 1 minute; 72° C., 2minutes; 72° C., 10 minutes

[0101] A 1.0 Kb PCR fragment of predicated size was isolated and clonedinto the pCRII-TOPO™ vector (Invitrogen) and completely sequenced(SEQ.ID.NO.: 7) using the T7 DNA sequenase kit (Amsham).

Example 2 Receptor Expression

[0102] Although a variety of cells are available to the art for theexpression of proteins, it is most preferred that mammalian cells beutilized. The primary reason for this is predicated upon practicalities,i.e., utilization of, e.g., yeast cells for the expression of a GPCR,while possible, introduces into the protocol a non-mammalian cell whichmay not (indeed, in the case of yeast, does not) include thereceptor-coupling, genetic-mechanism and secretary pathways that haveevolved for mammalian systems—thus, results obtained in non-mammaliancells, while of potential use, are not as preferred as that obtainedfrom mammalian cells. Of the mammalian cells, COS-7, 293 and 293T cellsare particularly preferred, although the specific mammalian cellutilized can be predicated upon the particular needs of the artisan. Thegeneral procedure for expression of the disclosed GPCRs is as follows.

[0103] On day one, 1×10⁷ 293T cells per 150 mm plate were plated out. Onday two, two reaction tubes will be prepared (the proportions to followfor each tube are per plate): tube A will be prepared by mixing 20 μgDNA (e.g., pCMV vector; pCMV vector with receptor cDNA, etc.) in 1.2 mlserum free DMEM (Irvine Scientific, Irvine, Calif.); tube B will beprepared by mixing 120 μl lipofectamine (Gibco BRL) in 1.2 ml serum freeDMEM. Tubes A and B are admixed by inversions (several times), followedby incubation at room temperature for 30-45 min. The admixture can bereferred to as the “transfection mixture”. Plated 293T cells are washedwith 1XPBS, followed by addition of 10 ml serum free DMEM. 2.4 ml of thetransfection mixture will then be added to the cells, followed byincubation for 4 hrs at 37° C./5% CO₂. The transfection mixture was thenbe removed by aspiration, followed by the addition of 25 ml of DMEM/10%Fetal Bovine Serum. Cells will then be incubated at 37° C./5% CO₂. After72 hr incubation, cells can then be harvested and utilized for analysis.

Example 3 Tissue Distribution of the Disclosed Human GPCRS

[0104] Several approaches can be used for determination of the tissuedistribution of the GPCRs disclosed herein.

[0105] 1. Dot-Blot Analysis

[0106] Using a commercially available human-tissue dot-blot format,endogenous orphan GPCRs were probed for a determination of the areaswhere such receptors are localized. cDNA fragments from the GPCRs ofExample 1 (radiolabelled) were (or can be) used as the probe:radiolabeled probe was (or can be) generated using the complete receptorcDNA (excised from the vector) using a Prime-It II™ Random PrimerLabeling Kit (Stratagene, #300385), according to manufacturer'sinstructions. A human RNA Master Blot™ (Clontech, #7770-1) washybridized with the endogenous human GPCR radiolabeled probe and washedunder stringent conditions according manufacturer's instructions. Theblot was exposed to Kodak BioMax™ Autoradiography film overnight at −80°C. Results are summarized for several receptors in Table B and C (seeFIGS. 1A and 1B for a grid identifying the various tissues and theirlocations, respectively). Exemplary dot-blots are provided in FIG. 2Aand 2B for results derived using hCHN3 and hCHN8, respectively. TABLE BORPHAN Tissue Distribution GPCR (highest levels, relative to othertissues in the dot-blot) hGPCR27 Fetal brain, Putamen, Pituitary gland,Caudate nucleus hARE-1 Spleen, Peripheral leukocytes, Fetal spleen hPPR1Pituitary gland, Heart, salivary gland, Small intestine, Testis hRUP3Pancreas hCHN3 Fetal brain, Putamen, Occipital cortex hCHN9 Pancreas,Small intestine, Liver hCHN10 Kidney, Thryoid

[0107] TABLE C Tissue Distribution ORPHAN GPCR (highest levels, relativeto other tissues in the dot-blot) hARE-3 Cerebellum left, Cerebellumright, Testis, Accumbens hGPCR3 Corpus collusum, Caudate nucleus, Liver,Heart, Inter- Ventricular Septum hARE-2 Cerebellum left, Cerebellumright, Substantia hCHN8 Cerebellum left, Cerebellum right, Kidney, Lung

[0108] 2. RT-PCR

[0109] a. hRUP3

[0110] To ascertain the tissue distribution of hRUP3 mRNA, RT-PCR wasperformed using hRUP3-specific primers and human multiple tissue cDNApanels (MTC, Clontech) as templates. Taq DNA polymerase (Stratagene) wasutilized for the PCR reaction, using the following reaction cycles in a40 ul reaction: 94° C. for 2 min; 94° C. for 15 sec; 55° C. for 30 sec;72° C. for 1 min; 72° C., for 10 min. Primers were as follows:5′-GACAGGTACCTTGCCATCAAG-3′; (SEQ.ID.NO.: 61; sense)5′-CTGCACAATGCCAGTGATAAGG-3′; (SEQ.ID.NO.: 62; antisense).

[0111] 20 ul of the reaction was loaded onto a 1% agarose gel; resultsare set forth in FIG. 3.

[0112] As is supported by the data of FIG. 3, of the 16 human tissues inthe cDNA panel utilized (brain, colon, heart, kidney, lung, ovary,pancreas, placenta, prostate, skeleton, small intestine, spleen, testis,thymus leukocyte, and liver) a single hRUP3 band is evident only fromthe pancreas. Additional comparative analysis of the protein sequence ofhRUP3 with other GPCRs suggest that hRUP3 is related to GPCRs havingsmall molecule endogenous ligand such that it is predicted that theendogenous ligand for hRUP3 is a small molecule.

[0113] b. hRUP4

[0114] RT-PCR was performed using hRUP4 oligo's 8 and 4 as primers andthe human multiple tissue cDNA panels (MTC, Clontech) as templates. TaqDNA polymerase (Stratagene) was used for the amplification in a 40 ulreaction by the following cycles: 94° C. for 30 seconds, 94° C. for 10seconds, 55° C. for 30 seconds, 72° C. for 2 minutes, and 72° C. for 5minutes with cycles 2 through 4 repeated 30 times.

[0115] 20 μl of the reaction were loaded on a 1% agarose gel to analyzethe RT-PCR products, and hRUP4 mRNA was found expressed in many humantissues, with the strongest expression in heart and kidney. (see, FIG.4). To confirm the authenticity of the PCR fragments, a 300 bp fragmentderived from the 5′ end of hRUP4 was used as a probe for the SouthernBlot analysis. The probe was labeled with ³²P-dCTP using the Prime-ItII™ Random Primer Labeling Kit (Stratagene) and purified using theProbeQuant™ G-50 micro columns (Amersham). Hybridization was doneovernight at 42° C. following a 12 hr pre-hybridization. The blot wasfinally washed at 65° C. with 0.1×SSC. The Southern blot did confirm thePCR fragments as hRUP4.

[0116] c. hRUP5

[0117] RT-PCR was performed using the following hRUP5 specific primers:5′-CTGACTTCTTGTTCCTGGCAGCAGCGG-3′; (SEQ.ID.NO.: 63; sense)5′-AGACCAGCCAGGGCACGCTGAAGAGTG-3′; (SEQ.ID.NO.: 64; antisense)

[0118] and the human multiple tissue cDNA panels (MTC, Clontech) astemplates. Taq DNA polymerase (Stratagene) was used for theamplification in a 40 ul reaction by the following cycles: 94° C. for 30sec, 94° C. for 10 sec, 62° C. for 1.5 min, 72° C. for 5 min, and withcycles 2 through 3 repeated 30 times. 20 μl of the reaction were loadedon a 1.5% agarose gel to analyze the RT-PCR products, and hRUP5 mRNA wasfound expressed only in the peripheral blood leukocytes (data notshown).

[0119] d. hRUP6

[0120] RT-PCR was applied to confirm the expression and to determine thetissue distribution of hRUP6. Oligonucleotides used, based on analignment of AC005871 and GPR66 segments, had the following sequences:5′-CCAACACCAGCATCCATGGCATCAAG-3′; (SEQ.ID.NO.: 73; sense),5′-GGAGAGTCAGCTCTGAAAGAATTCAGG-3′; (SEQ.ID.NO.: 74; antisense)

[0121] and the human multiple tissue cDNA panels (MTC, Clontech) wereused as templates. PCR was performed using TaqPlus Precision™ polymerase(Stratagene; manufacturing instructions will be followed) in a 40 ulreaction by the following cycles: 94° C. for 30 sec; 94° C. 5 sec; 66°C. for 40 sec, 72° C. for 2.5 min, and 72° C. for 7 min. Cycles 2through 4 were repeated 30 times.

[0122] 20 ul of the reaction were loaded on a 1.2% agarose gel toanalyze the RT-PCR products, and a specific 760 bp DNA fragmentrepresenting hRUP6 was expressed predominantly in the thymus and withless expression in the heart, kidney, lung, prostate small intestine andtestis. (see, FIG. 5).

[0123] References, including but limited to patent applications, thatare cited throughout this patent document, unless otherwise indicated,are incorporated herein by reference. Modifications and extension of thedisclosed inventions that are within the purview of the skilled artisanare encompassed within the above disclosure and the claims that follow.

[0124] Although a variety of Vectors are available to those in the art,for purposes of utilization for both endogenous and non-endogenous humanGPCRs, it is most preferred that the Vector utilized be pCMV. Thisvector was deposited with the American Type Culture Collection (ATCC) onOct. 13, 1998 (10801 University Blvd., Manassas, Va. 20110-2209 USA)under the provisions of the Budapest Treaty for the InternationalRecognition of the Deposit of Microorganisms for the Purpose of PatentProcedure. The DNA was tested by the ATCC and determined to be. The ATCChas assigned the following deposit number to pCMV: ATCC #203351.

1 74 1 1260 DNA Homo sapiens 1 atggtcttct cggcagtgtt gactgcgttccataccggga catccaacac aacatttgtc 60 gtgtatgaaa acacctacat gaatattacactccctccac cattccagca tcctgacctc 120 agtccattgc ttagatatag ttttgaaaccatggctccca ctggtttgag ttccttgacc 180 gtgaatagta cagctgtgcc cacaacaccagcagcattta agagcctaaa cttgcctctt 240 cagatcaccc tttctgctat aatgatattcattctgtttg tgtcttttct tgggaacttg 300 gttgtttgcc tcatggttta ccaaaaagctgccatgaggt ctgcaattaa catcctcctt 360 gccagcctag cttttgcaga catgttgcttgcagtgctga acatgccctt tgccctggta 420 actattctta ctacccgatg gatttttgggaaattcttct gtagggtatc tgctatgttt 480 ttctggttat ttgtgataga aggagtagccatcctgctca tcattagcat agataggttc 540 cttattatag tccagaggca ggataagctaaacccatata gagctaaggt tctgattgca 600 gtttcttggg caacttcctt ttgtgtagcttttcctttag ccgtaggaaa ccccgacctg 660 cagatacctt cccgagctcc ccagtgtgtgtttgggtaca caaccaatcc aggctaccag 720 gcttatgtga ttttgatttc tctcatttctttcttcatac ccttcctggt aatactgtac 780 tcatttatgg gcatactcaa cacccttcggcacaatgcct tgaggatcca tagctaccct 840 gaaggtatat gcctcagcca ggccagcaaactgggtctca tgagtctgca gagacctttc 900 cagatgagca ttgacatggg ctttaaaacacgtgccttca ccactatttt gattctcttt 960 gctgtcttca ttgtctgctg ggccccattcaccacttaca gccttgtggc aacattcagt 1020 aagcactttt actatcagca caacttttttgagattagca cctggctact gtggctctgc 1080 tacctcaagt ctgcattgaa tccgctgatctactactgga ggattaagaa attccatgat 1140 gcttgcctgg acatgatgcc taagtccttcaagtttttgc cgcagctccc tggtcacaca 1200 aagcgacgga tacgtcctag tgctgtctatgtgtgtgggg aacatcggac ggtggtgtga 1260 2 419 PRT Homo sapiens 2 Met ValPhe Ser Ala Val Leu Thr Ala Phe His Thr Gly Thr Ser Asn 1 5 10 15 ThrThr Phe Val Val Tyr Glu Asn Thr Tyr Met Asn Ile Thr Leu Pro 20 25 30 ProPro Phe Gln His Pro Asp Leu Ser Pro Leu Leu Arg Tyr Ser Phe 35 40 45 GluThr Met Ala Pro Thr Gly Leu Ser Ser Leu Thr Val Asn Ser Thr 50 55 60 AlaVal Pro Thr Thr Pro Ala Ala Phe Lys Ser Leu Asn Leu Pro Leu 65 70 75 80Gln Ile Thr Leu Ser Ala Ile Met Ile Phe Ile Leu Phe Val Ser Phe 85 90 95Leu Gly Asn Leu Val Val Cys Leu Met Val Tyr Gln Lys Ala Ala Met 100 105110 Arg Ser Ala Ile Asn Ile Leu Leu Ala Ser Leu Ala Phe Ala Asp Met 115120 125 Leu Leu Ala Val Leu Asn Met Pro Phe Ala Leu Val Thr Ile Leu Thr130 135 140 Thr Arg Trp Ile Phe Gly Lys Phe Phe Cys Arg Val Ser Ala MetPhe 145 150 155 160 Phe Trp Leu Phe Val Ile Glu Gly Val Ala Ile Leu LeuIle Ile Ser 165 170 175 Ile Asp Arg Phe Leu Ile Ile Val Gln Arg Gln AspLys Leu Asn Pro 180 185 190 Tyr Arg Ala Lys Val Leu Ile Ala Val Ser TrpAla Thr Ser Phe Cys 195 200 205 Val Ala Phe Pro Leu Ala Val Gly Asn ProAsp Leu Gln Ile Pro Ser 210 215 220 Arg Ala Pro Gln Cys Val Phe Gly TyrThr Thr Asn Pro Gly Tyr Gln 225 230 235 240 Ala Tyr Val Ile Leu Ile SerLeu Ile Ser Phe Phe Ile Pro Phe Leu 245 250 255 Val Ile Leu Tyr Ser PheMet Gly Ile Leu Asn Thr Leu Arg His Asn 260 265 270 Ala Leu Arg Ile HisSer Tyr Pro Glu Gly Ile Cys Leu Ser Gln Ala 275 280 285 Ser Lys Leu GlyLeu Met Ser Leu Gln Arg Pro Phe Gln Met Ser Ile 290 295 300 Asp Met GlyPhe Lys Thr Arg Ala Phe Thr Thr Ile Leu Ile Leu Phe 305 310 315 320 AlaVal Phe Ile Val Cys Trp Ala Pro Phe Thr Thr Tyr Ser Leu Val 325 330 335Ala Thr Phe Ser Lys His Phe Tyr Tyr Gln His Asn Phe Phe Glu Ile 340 345350 Ser Thr Trp Leu Leu Trp Leu Cys Tyr Leu Lys Ser Ala Leu Asn Pro 355360 365 Leu Ile Tyr Tyr Trp Arg Ile Lys Lys Phe His Asp Ala Cys Leu Asp370 375 380 Met Met Pro Lys Ser Phe Lys Phe Leu Pro Gln Leu Pro Gly HisThr 385 390 395 400 Lys Arg Arg Ile Arg Pro Ser Ala Val Tyr Val Cys GlyGlu His Arg 405 410 415 Thr Val Val 3 1119 DNA Homo sapiens 3 atgttagccaacagctcctc aaccaacagt tctgttctcc cgtgtcctga ctaccgacct 60 acccaccgcctgcacttggt ggtctacagc ttggtgctgg ctgccgggct ccccctcaac 120 gcgctagccctctgggtctt cctgcgcgcg ctgcgcgtgc actcggtggt gagcgtgtac 180 atgtgtaacctggcggccag cgacctgctc ttcaccctct cgctgcccgt tcgtctctcc 240 tactacgcactgcaccactg gcccttcccc gacctcctgt gccagacgac gggcgccatc 300 ttccagatgaacatgtacgg cagctgcatc ttcctgatgc tcatcaacgt ggaccgctac 360 gccgccatcgtgcacccgct gcgactgcgc cacctgcggc ggccccgcgt ggcgcggctg 420 ctctgcctgggcgtgtgggc gctcatcctg gtgtttgccg tgcccgccgc ccgcgtgcac 480 aggccctcgcgttgccgcta ccgggacctc gaggtgcgcc tatgcttcga gagcttcagc 540 gacgagctgtggaaaggcag gctgctgccc ctcgtgctgc tggccgaggc gctgggcttc 600 ctgctgcccctggcggcggt ggtctactcg tcgggccgag tcttctggac gctggcgcgc 660 cccgacgccacgcagagcca gcggcggcgg aagaccgtgc gcctcctgct ggctaacctc 720 gtcatcttcctgctgtgctt cgtgccctac aacagcacgc tggcggtcta cgggctgctg 780 cggagcaagctggtggcggc cagcgtgcct gcccgcgatc gcgtgcgcgg ggtgctgatg 840 gtgatggtgctgctggccgg cgccaactgc gtgctggacc cgctggtgta ctactttagc 900 gccgagggcttccgcaacac cctgcgcggc ctgggcactc cgcaccgggc caggacctcg 960 gccaccaacgggacgcgggc ggcgctcgcg caatccgaaa ggtccgccgt caccaccgac 1020 gccaccaggccggatgccgc cagtcagggg ctgctccgac cctccgactc ccactctctg 1080 tcttccttcacacagtgtcc ccaggattcc gccctctga 1119 4 372 PRT Homo sapiens 4 Met LeuAla Asn Ser Ser Ser Thr Asn Ser Ser Val Leu Pro Cys Pro 1 5 10 15 AspTyr Arg Pro Thr His Arg Leu His Leu Val Val Tyr Ser Leu Val 20 25 30 LeuAla Ala Gly Leu Pro Leu Asn Ala Leu Ala Leu Trp Val Phe Leu 35 40 45 ArgAla Leu Arg Val His Ser Val Val Ser Val Tyr Met Cys Asn Leu 50 55 60 AlaAla Ser Asp Leu Leu Phe Thr Leu Ser Leu Pro Val Arg Leu Ser 65 70 75 80Tyr Tyr Ala Leu His His Trp Pro Phe Pro Asp Leu Leu Cys Gln Thr 85 90 95Thr Gly Ala Ile Phe Gln Met Asn Met Tyr Gly Ser Cys Ile Phe Leu 100 105110 Met Leu Ile Asn Val Asp Arg Tyr Ala Ala Ile Val His Pro Leu Arg 115120 125 Leu Arg His Leu Arg Arg Pro Arg Val Ala Arg Leu Leu Cys Leu Gly130 135 140 Val Trp Ala Leu Ile Leu Val Phe Ala Val Pro Ala Ala Arg ValHis 145 150 155 160 Arg Pro Ser Arg Cys Arg Tyr Arg Asp Leu Glu Val ArgLeu Cys Phe 165 170 175 Glu Ser Phe Ser Asp Glu Leu Trp Lys Gly Arg LeuLeu Pro Leu Val 180 185 190 Leu Leu Ala Glu Ala Leu Gly Phe Leu Leu ProLeu Ala Ala Val Val 195 200 205 Tyr Ser Ser Gly Arg Val Phe Trp Thr LeuAla Arg Pro Asp Ala Thr 210 215 220 Gln Ser Gln Arg Arg Arg Lys Thr ValArg Leu Leu Leu Ala Asn Leu 225 230 235 240 Val Ile Phe Leu Leu Cys PheVal Pro Tyr Asn Ser Thr Leu Ala Val 245 250 255 Tyr Gly Leu Leu Arg SerLys Leu Val Ala Ala Ser Val Pro Ala Arg 260 265 270 Asp Arg Val Arg GlyVal Leu Met Val Met Val Leu Leu Ala Gly Ala 275 280 285 Asn Cys Val LeuAsp Pro Leu Val Tyr Tyr Phe Ser Ala Glu Gly Phe 290 295 300 Arg Asn ThrLeu Arg Gly Leu Gly Thr Pro His Arg Ala Arg Thr Ser 305 310 315 320 AlaThr Asn Gly Thr Arg Ala Ala Leu Ala Gln Ser Glu Arg Ser Ala 325 330 335Val Thr Thr Asp Ala Thr Arg Pro Asp Ala Ala Ser Gln Gly Leu Leu 340 345350 Arg Pro Ser Asp Ser His Ser Leu Ser Ser Phe Thr Gln Cys Pro Gln 355360 365 Asp Ser Ala Leu 370 5 1107 DNA Homo sapiens 5 atggccaactccacagggct gaacgcctca gaagtcgcag gctcgttggg gttgatcctg 60 gcagctgtcgtggaggtggg ggcactgctg ggcaacggcg cgctgctggt cgtggtgctg 120 cgcacgccgggactgcgcga cgcgctctac ctggcgcacc tgtgcgtcgt ggacctgctg 180 gcggccgcctccatcatgcc gctgggcctg ctggccgcac cgccgcccgg gctgggccgc 240 gtgcgcctgggccccgcgcc atgccgcgcc gctcgcttcc tctccgccgc tctgctgccg 300 gcctgcacgctcggggtggc cgcacttggc ctggcacgct accgcctcat cgtgcacccg 360 ctgcggccaggctcgcggcc gccgcctgtg ctcgtgctca ccgccgtgtg ggccgcggcg 420 ggactgctgggcgcgctctc cctgctcggc ccgccgcccg caccgccccc tgctcctgct 480 cgctgctcggtcctggctgg gggcctcggg cccttccggc cgctctgggc cctgctggcc 540 ttcgcgctgcccgccctcct gctgctcggc gcctacggcg gcatcttcgt ggtggcgcgt 600 cgcgctgccctgaggccccc acggccggcg cgcgggtccc gactccgctc ggactctctg 660 gatagccgcctttccatctt gccgccgctc cggcctcgcc tgcccggggg caaggcggcc 720 ctggccccagcgctggccgt gggccaattt gcagcctgct ggctgcctta tggctgcgcg 780 tgcctggcgcccgcagcgcg ggccgcggaa gccgaagcgg ctgtcacctg ggtcgcctac 840 tcggccttcgcggctcaccc cttcctgtac gggctgctgc agcgccccgt gcgcttggca 900 ctgggccgcctctctcgccg tgcactgcct ggacctgtgc gggcctgcac tccgcaagcc 960 tggcacccgcgggcactctt gcaatgcctc cagagacccc cagagggccc tgccgtaggc 1020 ccttctgaggctccagaaca gacccccgag ttggcaggag ggcggagccc cgcataccag 1080 gggccacctgagagttctct ctcctga 1107 6 368 PRT Homo sapiens 6 Met Ala Asn Ser Thr GlyLeu Asn Ala Ser Glu Val Ala Gly Ser Leu 1 5 10 15 Gly Leu Ile Leu AlaAla Val Val Glu Val Gly Ala Leu Leu Gly Asn 20 25 30 Gly Ala Leu Leu ValVal Val Leu Arg Thr Pro Gly Leu Arg Asp Ala 35 40 45 Leu Tyr Leu Ala HisLeu Cys Val Val Asp Leu Leu Ala Ala Ala Ser 50 55 60 Ile Met Pro Leu GlyLeu Leu Ala Ala Pro Pro Pro Gly Leu Gly Arg 65 70 75 80 Val Arg Leu GlyPro Ala Pro Cys Arg Ala Ala Arg Phe Leu Ser Ala 85 90 95 Ala Leu Leu ProAla Cys Thr Leu Gly Val Ala Ala Leu Gly Leu Ala 100 105 110 Arg Tyr ArgLeu Ile Val His Pro Leu Arg Pro Gly Ser Arg Pro Pro 115 120 125 Pro ValLeu Val Leu Thr Ala Val Trp Ala Ala Ala Gly Leu Leu Gly 130 135 140 AlaLeu Ser Leu Leu Gly Pro Pro Pro Ala Pro Pro Pro Ala Pro Ala 145 150 155160 Arg Cys Ser Val Leu Ala Gly Gly Leu Gly Pro Phe Arg Pro Leu Trp 165170 175 Ala Leu Leu Ala Phe Ala Leu Pro Ala Leu Leu Leu Leu Gly Ala Tyr180 185 190 Gly Gly Ile Phe Val Val Ala Arg Arg Ala Ala Leu Arg Pro ProArg 195 200 205 Pro Ala Arg Gly Ser Arg Leu Arg Ser Asp Ser Leu Asp SerArg Leu 210 215 220 Ser Ile Leu Pro Pro Leu Arg Pro Arg Leu Pro Gly GlyLys Ala Ala 225 230 235 240 Leu Ala Pro Ala Leu Ala Val Gly Gln Phe AlaAla Cys Trp Leu Pro 245 250 255 Tyr Gly Cys Ala Cys Leu Ala Pro Ala AlaArg Ala Ala Glu Ala Glu 260 265 270 Ala Ala Val Thr Trp Val Ala Tyr SerAla Phe Ala Ala His Pro Phe 275 280 285 Leu Tyr Gly Leu Leu Gln Arg ProVal Arg Leu Ala Leu Gly Arg Leu 290 295 300 Ser Arg Arg Ala Leu Pro GlyPro Val Arg Ala Cys Thr Pro Gln Ala 305 310 315 320 Trp His Pro Arg AlaLeu Leu Gln Cys Leu Gln Arg Pro Pro Glu Gly 325 330 335 Pro Ala Val GlyPro Ser Glu Ala Pro Glu Gln Thr Pro Glu Leu Ala 340 345 350 Gly Gly ArgSer Pro Ala Tyr Gln Gly Pro Pro Glu Ser Ser Leu Ser 355 360 365 7 1008DNA Homo sapiens 7 atggaatcat ctttctcatt tggagtgatc cttgctgtcctggcctccct catcattgct 60 actaacacac tagtggctgt ggctgtgctg ctgttgatccacaagaatga tggtgtcagt 120 ctctgcttca ccttgaatct ggctgtggct gacaccttgattggtgtggc catctctggc 180 ctactcacag accagctctc cagcccttct cggcccacacagaagaccct gtgcagcctg 240 cggatggcat ttgtcacttc ctccgcagct gcctctgtcctcacggtcat gctgatcacc 300 tttgacaggt accttgccat caagcagccc ttccgctacttgaagatcat gagtgggttc 360 gtggccgggg cctgcattgc cgggctgtgg ttagtgtcttacctcattgg cttcctccca 420 ctcggaatcc ccatgttcca gcagactgcc tacaaagggcagtgcagctt ctttgctgta 480 tttcaccctc acttcgtgct gaccctctcc tgcgttggcttcttcccagc catgctcctc 540 tttgtcttct tctactgcga catgctcaag attgcctccatgcacagcca gcagattcga 600 aagatggaac atgcaggagc catggctgga ggttatcgatccccacggac tcccagcgac 660 ttcaaagctc tccgtactgt gtctgttctc attgggagctttgctctatc ctggaccccc 720 ttccttatca ctggcattgt gcaggtggcc tgccaggagtgtcacctcta cctagtgctg 780 gaacggtacc tgtggctgct cggcgtgggc aactccctgctcaacccact catctatgcc 840 tattggcaga aggaggtgcg actgcagctc taccacatggccctaggagt gaagaaggtg 900 ctcacctcat tcctcctctt tctctcggcc aggaattgtggcccagagag gcccagggaa 960 agttcctgtc acatcgtcac tatctccagc tcagagtttgatggctaa 1008 8 335 PRT Homo sapiens 8 Met Glu Ser Ser Phe Ser Phe GlyVal Ile Leu Ala Val Leu Ala Ser 1 5 10 15 Leu Ile Ile Ala Thr Asn ThrLeu Val Ala Val Ala Val Leu Leu Leu 20 25 30 Ile His Lys Asn Asp Gly ValSer Leu Cys Phe Thr Leu Asn Leu Ala 35 40 45 Val Ala Asp Thr Leu Ile GlyVal Ala Ile Ser Gly Leu Leu Thr Asp 50 55 60 Gln Leu Ser Ser Pro Ser ArgPro Thr Gln Lys Thr Leu Cys Ser Leu 65 70 75 80 Arg Met Ala Phe Val ThrSer Ser Ala Ala Ala Ser Val Leu Thr Val 85 90 95 Met Leu Ile Thr Phe AspArg Tyr Leu Ala Ile Lys Gln Pro Phe Arg 100 105 110 Tyr Leu Lys Ile MetSer Gly Phe Val Ala Gly Ala Cys Ile Ala Gly 115 120 125 Leu Trp Leu ValSer Tyr Leu Ile Gly Phe Leu Pro Leu Gly Ile Pro 130 135 140 Met Phe GlnGln Thr Ala Tyr Lys Gly Gln Cys Ser Phe Phe Ala Val 145 150 155 160 PheHis Pro His Phe Val Leu Thr Leu Ser Cys Val Gly Phe Phe Pro 165 170 175Ala Met Leu Leu Phe Val Phe Phe Tyr Cys Asp Met Leu Lys Ile Ala 180 185190 Ser Met His Ser Gln Gln Ile Arg Lys Met Glu His Ala Gly Ala Met 195200 205 Ala Gly Gly Tyr Arg Ser Pro Arg Thr Pro Ser Asp Phe Lys Ala Leu210 215 220 Arg Thr Val Ser Val Leu Ile Gly Ser Phe Ala Leu Ser Trp ThrPro 225 230 235 240 Phe Leu Ile Thr Gly Ile Val Gln Val Ala Cys Gln GluCys His Leu 245 250 255 Tyr Leu Val Leu Glu Arg Tyr Leu Trp Leu Leu GlyVal Gly Asn Ser 260 265 270 Leu Leu Asn Pro Leu Ile Tyr Ala Tyr Trp GlnLys Glu Val Arg Leu 275 280 285 Gln Leu Tyr His Met Ala Leu Gly Val LysLys Val Leu Thr Ser Phe 290 295 300 Leu Leu Phe Leu Ser Ala Arg Asn CysGly Pro Glu Arg Pro Arg Glu 305 310 315 320 Ser Ser Cys His Ile Val ThrIle Ser Ser Ser Glu Phe Asp Gly 325 330 335 9 1413 DNA Homo sapiens 9atggacacta ccatggaagc tgacctgggt gccactggcc acaggccccg cacagagctt 60gatgatgagg actcctaccc ccaaggtggc tgggacacgg tcttcctggt ggccctgctg 120ctccttgggc tgccagccaa tgggttgatg gcgtggctgg ccggctccca ggcccggcat 180ggagctggca cgcgtctggc gctgctcctg ctcagcctgg ccctctctga cttcttgttc 240ctggcagcag cggccttcca gatcctagag atccggcatg ggggacactg gccgctgggg 300acagctgcct gccgcttcta ctacttccta tggggcgtgt cctactcctc cggcctcttc 360ctgctggccg ccctcagcct cgaccgctgc ctgctggcgc tgtgcccaca ctggtaccct 420gggcaccgcc cagtccgcct gcccctctgg gtctgcgccg gtgtctgggt gctggccaca 480ctcttcagcg tgccctggct ggtcttcccc gaggctgccg tctggtggta cgacctggtc 540atctgcctgg acttctggga cagcgaggag ctgtcgctga ggatgctgga ggtcctgggg 600ggcttcctgc ctttcctcct gctgctcgtc tgccacgtgc tcacccaggc cacagcctgt 660cgcacctgcc accgccaaca gcagcccgca gcctgccggg gcttcgcccg tgtggccagg 720accattctgt cagcctatgt ggtcctgagg ctgccctacc agctggccca gctgctctac 780ctggccttcc tgtgggacgt ctactctggc tacctgctct gggaggccct ggtctactcc 840gactacctga tcctactcaa cagctgcctc agccccttcc tctgcctcat ggccagtgcc 900gacctccgga ccctgctgcg ctccgtgctc tcgtccttcg cggcagctct ctgcgaggag 960cggccgggca gcttcacgcc cactgagcca cagacccagc tagattctga gggtccaact 1020ctgccagagc cgatggcaga ggcccagtca cagatggatc ctgtggccca gcctcaggtg 1080aaccccacac tccagccacg atcggatccc acagctcagc cacagctgaa ccctacggcc 1140cagccacagt cggatcccac agcccagcca cagctgaacc tcatggccca gccacagtca 1200gattctgtgg cccagccaca ggcagacact aacgtccaga cccctgcacc tgctgccagt 1260tctgtgccca gtccctgtga tgaagcttcc ccaaccccat cctcgcatcc taccccaggg 1320gcccttgagg acccagccac acctcctgcc tctgaaggag aaagccccag cagcaccccg 1380ccagaggcgg ccccgggcgc aggccccacg tga 1413 10 468 PRT Homo sapiens 10 MetAsp Thr Thr Met Glu Ala Asp Leu Gly Ala Thr Gly His Arg Pro 1 5 10 15Arg Thr Glu Leu Asp Asp Glu Asp Ser Tyr Pro Gln Gly Gly Trp Asp 20 25 30Thr Val Phe Leu Val Ala Leu Leu Leu Leu Gly Leu Pro Ala Asn Gly 35 40 45Leu Met Ala Trp Leu Ala Gly Ser Gln Ala Arg His Gly Ala Gly Thr 50 55 60Arg Leu Ala Leu Leu Leu Leu Ser Leu Ala Leu Ser Asp Phe Leu Phe 65 70 7580 Leu Ala Ala Ala Ala Phe Gln Ile Leu Glu Ile Arg His Gly Gly His 85 9095 Trp Pro Leu Gly Thr Ala Ala Cys Arg Phe Tyr Tyr Phe Leu Trp Gly 100105 110 Val Ser Tyr Ser Ser Gly Leu Phe Leu Leu Ala Ala Leu Ser Leu Asp115 120 125 Arg Cys Leu Leu Ala Leu Cys Pro His Trp Tyr Pro Gly His ArgPro 130 135 140 Val Arg Leu Pro Leu Trp Val Cys Ala Gly Val Trp Val LeuAla Thr 145 150 155 160 Leu Phe Ser Val Pro Trp Leu Val Phe Pro Glu AlaAla Val Trp Trp 165 170 175 Tyr Asp Leu Val Ile Cys Leu Asp Phe Trp AspSer Glu Glu Leu Ser 180 185 190 Leu Arg Met Leu Glu Val Leu Gly Gly PheLeu Pro Phe Leu Leu Leu 195 200 205 Leu Val Cys His Val Leu Thr Gln AlaThr Arg Thr Cys His Arg Gln 210 215 220 Gln Gln Pro Ala Ala Cys Arg GlyPhe Ala Arg Val Ala Arg Thr Ile 225 230 235 240 Leu Ser Ala Tyr Val ValLeu Arg Leu Pro Tyr Gln Leu Ala Gln Leu 245 250 255 Leu Tyr Leu Ala PheLeu Trp Asp Val Tyr Ser Gly Tyr Leu Leu Trp 260 265 270 Glu Ala Leu ValTyr Ser Asp Tyr Leu Ile Leu Leu Asn Ser Cys Leu 275 280 285 Ser Pro PheLeu Cys Leu Met Ala Ser Ala Asp Leu Arg Thr Leu Leu 290 295 300 Arg SerVal Leu Ser Ser Phe Ala Ala Ala Leu Cys Glu Glu Arg Pro 305 310 315 320Gly Ser Phe Thr Pro Thr Glu Pro Gln Thr Gln Leu Asp Ser Glu Gly 325 330335 Pro Thr Leu Pro Glu Pro Met Ala Glu Ala Gln Ser Gln Met Asp Pro 340345 350 Val Ala Gln Pro Gln Val Asn Pro Thr Leu Gln Pro Arg Ser Asp Pro355 360 365 Thr Ala Gln Pro Gln Leu Asn Pro Thr Ala Gln Pro Gln Ser AspPro 370 375 380 Thr Ala Gln Pro Gln Leu Asn Leu Met Ala Gln Pro Gln SerAsp Ser 385 390 395 400 Val Ala Gln Pro Gln Ala Asp Thr Asn Val Gln ThrPro Ala Pro Ala 405 410 415 Ala Ser Ser Val Pro Ser Pro Cys Asp Glu AlaSer Pro Thr Pro Ser 420 425 430 Ser His Pro Thr Pro Gly Ala Leu Glu AspPro Ala Thr Pro Pro Ala 435 440 445 Ser Glu Gly Glu Ser Pro Ser Ser ThrPro Pro Glu Ala Ala Pro Gly 450 455 460 Ala Gly Pro Thr 465 11 1248 DNAHomo sapiens 11 atgtcaggga tggaaaaact tcagaatgct tcctggatct accagcagaaactagaagat 60 ccattccaga aacacctgaa cagcaccgag gagtatctgg ccttcctctgcggacctcgg 120 cgcagccact tcttcctccc cgtgtctgtg gtgtatgtgc caatttttgtggtgggggtc 180 attggcaatg tcctggtgtg cctggtgatt ctgcagcacc aggctatgaagacgcccacc 240 aactactacc tcttcagcct ggcggtctct gacctcctgg tcctgctccttggaatgccc 300 ctggaggtct atgagatgtg gcgcaactac cctttcttgt tcgggcccgtgggctgctac 360 ttcaagacgg ccctctttga gaccgtgtgc ttcgcctcca tcctcagcatcaccaccgtc 420 agcgtggagc gctacgtggc catcctacac ccgttccgcg ccaaactgcagagcacccgg 480 cgccgggccc tcaggatcct cggcatcgtc tggggcttct ccgtgctcttctccctgccc 540 aacaccagca tccatggcat caagttccac tacttcccca atgggtccctggtcccaggt 600 tcggccacct gtacggtcat caagcccatg tggatctaca atttcatcatccaggtcacc 660 tccttcctat tctacctcct ccccatgact gtcatcagtg tcctctactacctcatggca 720 ctcagactaa agaaagacaa atctcttgag gcagatgaag ggaatgcaaatattcaaaga 780 ccctgcagaa aatcagtcaa caagatgctg tttgtcttgg tcttagtgtttgctatctgt 840 tgggccccgt tccacattga ccgactcttc ttcagctttg tggaggagtggagtgaatcc 900 ctggctgctg tgttcaacct cgtccatgtg gtgtcaggtg tcttcttctacctgagctca 960 gctgtcaacc ccattatcta taacctactg tctcgccgct tccaggcagcattccagaat 1020 gtgatctctt ctttccacaa acagtggcac tcccagcatg acccacagttgccacctgcc 1080 cagcggaaca tcttcctgac agaatgccac tttgtggagc tgaccgaagatataggtccc 1140 caattcccat gtcagtcatc catgcacaac tctcacctcc caacagccctctctagtgaa 1200 cagatgtcaa gaacaaacta tcaaagcttc cactttaaca aaacctga1248 12 415 PRT Homo sapiens 12 Met Ser Gly Met Glu Lys Leu Gln Asn AlaSer Trp Ile Tyr Gln Gln 1 5 10 15 Lys Leu Glu Asp Pro Phe Gln Lys HisLeu Asn Ser Thr Glu Glu Tyr 20 25 30 Leu Ala Phe Leu Cys Gly Pro Arg ArgSer His Phe Phe Leu Pro Val 35 40 45 Ser Val Val Tyr Val Pro Ile Phe ValVal Gly Val Ile Gly Asn Val 50 55 60 Leu Val Cys Leu Val Ile Leu Gln HisGln Ala Met Lys Thr Pro Thr 65 70 75 80 Asn Tyr Tyr Leu Phe Ser Leu AlaVal Ser Asp Leu Leu Val Leu Leu 85 90 95 Leu Gly Met Pro Leu Glu Val TyrGlu Met Trp Arg Asn Tyr Pro Phe 100 105 110 Leu Phe Gly Pro Val Gly CysTyr Phe Lys Thr Ala Leu Phe Glu Thr 115 120 125 Val Cys Phe Ala Ser IleLeu Ser Ile Thr Thr Val Ser Val Glu Arg 130 135 140 Tyr Val Ala Ile LeuHis Pro Phe Arg Ala Lys Leu Gln Ser Thr Arg 145 150 155 160 Arg Arg AlaLeu Arg Ile Leu Gly Ile Val Trp Gly Phe Ser Val Leu 165 170 175 Phe SerLeu Pro Asn Thr Ser Ile His Gly Ile Lys Phe His Tyr Phe 180 185 190 ProAsn Gly Ser Leu Val Pro Gly Ser Ala Thr Cys Thr Val Ile Lys 195 200 205Pro Met Trp Ile Tyr Asn Phe Ile Ile Gln Val Thr Ser Phe Leu Phe 210 215220 Tyr Leu Leu Pro Met Thr Val Ile Ser Val Leu Tyr Tyr Leu Met Ala 225230 235 240 Leu Arg Leu Lys Lys Asp Lys Ser Leu Glu Ala Asp Glu Gly AsnAla 245 250 255 Asn Ile Gln Arg Pro Cys Arg Lys Ser Val Asn Lys Met LeuPhe Val 260 265 270 Leu Val Leu Val Phe Ala Ile Cys Trp Ala Pro Phe HisIle Asp Arg 275 280 285 Leu Phe Phe Ser Phe Val Glu Glu Trp Ser Glu SerLeu Ala Ala Val 290 295 300 Phe Asn Leu Val His Val Val Ser Gly Val PhePhe Tyr Leu Ser Ser 305 310 315 320 Ala Val Asn Pro Ile Ile Tyr Asn LeuLeu Ser Arg Arg Phe Gln Ala 325 330 335 Ala Phe Gln Asn Val Ile Ser SerPhe His Lys Gln Trp His Ser Gln 340 345 350 His Asp Pro Gln Leu Pro ProAla Gln Arg Asn Ile Phe Leu Thr Glu 355 360 365 Cys His Phe Val Glu LeuThr Glu Asp Ile Gly Pro Gln Phe Pro Cys 370 375 380 Gln Ser Ser Met HisAsn Ser His Leu Pro Thr Ala Leu Ser Ser Glu 385 390 395 400 Gln Met SerArg Thr Asn Tyr Gln Ser Phe His Phe Asn Lys Thr 405 410 415 13 1173 DNAHomo sapiens 13 atgccagata ctaatagcac aatcaattta tcactaagca ctcgtgttactttagcattt 60 tttatgtcct tagtagcttt tgctataatg ctaggaaatg ctttggtcattttagctttt 120 gtggtggaca aaaaccttag acatcgaagt agttattttt ttcttaacttggccatctct 180 gacttctttg tgggtgtgat ctccattcct ttgtacatcc ctcacacgctgttcgaatgg 240 gattttggaa aggaaatctg tgtattttgg ctcactactg actatctgttatgtacagca 300 tctgtatata acattgtcct catcagctat gatcgatacc tgtcagtctcaaatgctgtg 360 tcttatagaa ctcaacatac tggggtcttg aagattgtta ctctgatggtggccgtttgg 420 gtgctggcct tcttagtgaa tgggccaatg attctagttt cagagtcttggaaggatgaa 480 ggtagtgaat gtgaacctgg atttttttcg gaatggtaca tccttgccatcacatcattc 540 ttggaattcg tgatcccagt catcttagtc gcttatttca acatgaatatttattggagc 600 ctgtggaagc gtgatcatct cagtaggtgc caaagccatc ctggactgactgctgtctct 660 tccaacatct gtggacactc attcagaggt agactatctt caaggagatctctttctgca 720 tcgacagaag ttcctgcatc ctttcattca gagagacaga ggagaaagagtagtctcatg 780 ttttcctcaa gaaccaagat gaatagcaat acaattgctt ccaaaatgggttccttctcc 840 caatcagatt ctgtagctct tcaccaaagg gaacatgttg aactgcttagagccaggaga 900 ttagccaagt cactggccat tctcttaggg gtttttgctg tttgctgggctccatattct 960 ctgttcacaa ttgtcctttc attttattcc tcagcaacag gtcctaaatcagtttggtat 1020 agaattgcat tttggcttca gtggttcaat tcctttgtca atcctcttttgtatccattg 1080 tgtcacaagc gctttcaaaa ggctttcttg aaaatatttt gtataaaaaagcaacctcta 1140 ccatcacaac acagtcggtc agtatcttct taa 1173 14 390 PRTHomo sapiens 14 Met Pro Asp Thr Asn Ser Thr Ile Asn Leu Ser Leu Ser ThrArg Val 1 5 10 15 Thr Leu Ala Phe Phe Met Ser Leu Val Ala Phe Ala IleMet Leu Gly 20 25 30 Asn Ala Leu Val Ile Leu Ala Phe Val Val Asp Lys AsnLeu Arg His 35 40 45 Arg Ser Ser Tyr Phe Phe Leu Asn Leu Ala Ile Ser AspPhe Phe Val 50 55 60 Gly Val Ile Ser Ile Pro Leu Tyr Ile Pro His Thr LeuPhe Glu Trp 65 70 75 80 Asp Phe Gly Lys Glu Ile Cys Val Phe Trp Leu ThrThr Asp Tyr Leu 85 90 95 Leu Cys Thr Ala Ser Val Tyr Asn Ile Val Leu IleSer Tyr Asp Arg 100 105 110 Tyr Leu Ser Val Ser Asn Ala Val Ser Tyr ArgThr Gln His Thr Gly 115 120 125 Val Leu Lys Ile Val Thr Leu Met Val AlaVal Trp Val Leu Ala Phe 130 135 140 Leu Val Asn Gly Pro Met Ile Leu ValSer Glu Ser Trp Lys Asp Glu 145 150 155 160 Gly Ser Glu Cys Glu Pro GlyPhe Phe Ser Glu Trp Tyr Ile Leu Ala 165 170 175 Ile Thr Ser Phe Leu GluPhe Val Ile Pro Val Ile Leu Val Ala Tyr 180 185 190 Phe Asn Met Asn IleTyr Trp Ser Leu Trp Lys Arg Asp His Leu Ser 195 200 205 Arg Cys Gln SerHis Pro Gly Leu Thr Ala Val Ser Ser Asn Ile Cys 210 215 220 Gly His SerPhe Arg Gly Arg Leu Ser Ser Arg Arg Ser Leu Ser Ala 225 230 235 240 SerThr Glu Val Pro Ala Ser Phe His Ser Glu Arg Gln Arg Arg Lys 245 250 255Ser Ser Leu Met Phe Ser Ser Arg Thr Lys Met Asn Ser Asn Thr Ile 260 265270 Ala Ser Lys Met Gly Ser Phe Ser Gln Ser Asp Ser Val Ala Leu His 275280 285 Gln Arg Glu His Val Glu Leu Leu Arg Ala Arg Arg Leu Ala Lys Ser290 295 300 Leu Ala Ile Leu Leu Gly Val Phe Ala Val Cys Trp Ala Pro TyrSer 305 310 315 320 Leu Phe Thr Ile Val Leu Ser Phe Tyr Ser Ser Ala ThrGly Pro Lys 325 330 335 Ser Val Trp Tyr Arg Ile Ala Phe Trp Leu Gln TrpPhe Asn Ser Phe 340 345 350 Val Asn Pro Leu Leu Tyr Pro Leu Cys His LysArg Phe Gln Lys Ala 355 360 365 Phe Leu Lys Ile Phe Cys Ile Lys Lys GlnPro Leu Pro Ser Gln His 370 375 380 Ser Arg Ser Val Ser Ser 385 390 151128 DNA Homo sapiens 15 atggcgaacg cgagcgagcc gggtggcagc ggcggcggcgaggcggccgc cctgggcctc 60 aagctggcca cgctcagcct gctgctgtgc gtgagcctagcgggcaacgt gctgttcgcg 120 ctgctgatcg tgcgggagcg cagcctgcac cgcgccccgtactacctgct gctcgacctg 180 tgcctggccg acgggctgcg cgcgctcgcc tgcctcccggccgtcatgct ggcggcgcgg 240 cgtgcggcgg ccgcggcggg ggcgccgccg ggcgcgctgggctgcaagct gctcgccttc 300 ctggccgcgc tcttctgctt ccacgccgcc ttcctgctgctgggcgtggg cgtcacccgc 360 tacctggcca tcgcgcacca ccgcttctat gcagagcgcctggccggctg gccgtgcgcc 420 gccatgctgg tgtgcgccgc ctgggcgctg gcgctggccgcggccttccc gccagtgctg 480 gacggcggtg gcgacgacga ggacgcgccg tgcgccctggagcagcggcc cgacggcgcc 540 cccggcgcgc tgggcttcct gctgctgctg gccgtggtggtgggcgccac gcacctcgtc 600 tacctccgcc tgctcttctt catccacgac cgccgcaagatgcggcccgc gcgcctggtg 660 cccgccgtca gccacgactg gaccttccac ggcccgggcgccaccggcca ggcggccgcc 720 aactggacgg cgggcttcgg ccgcgggccc acgccgcccgcgcttgtggg catccggccc 780 gcagggccgg gccgcggcgc gcgccgcctc ctcgtgctggaagaattcaa gacggagaag 840 aggctgtgca agatgttcta cgccgtcacg ctgctcttcctgctcctctg ggggccctac 900 gtcgtggcca gctacctgcg ggtcctggtg cggcccggcgccgtccccca ggcctacctg 960 acggcctccg tgtggctgac cttcgcgcag gccggcatcaaccccgtcgt gtgcttcctc 1020 ttcaacaggg agctgaggga ctgcttcagg gcccagttcccctgctgcca gagcccccgg 1080 accacccagg cgacccatcc ctgcgacctg aaaggcattggtttatga 1128 16 375 PRT Homo sapiens 16 Met Ala Asn Ala Ser Glu Pro GlyGly Ser Gly Gly Gly Glu Ala Ala 1 5 10 15 Ala Leu Gly Leu Lys Leu AlaThr Leu Ser Leu Leu Leu Cys Val Ser 20 25 30 Leu Ala Gly Asn Val Leu PheAla Leu Leu Ile Val Arg Glu Arg Ser 35 40 45 Leu His Arg Ala Pro Tyr TyrLeu Leu Leu Asp Leu Cys Leu Ala Asp 50 55 60 Gly Leu Arg Ala Leu Ala CysLeu Pro Ala Val Met Leu Ala Ala Arg 65 70 75 80 Arg Ala Ala Ala Ala AlaGly Ala Pro Pro Gly Ala Leu Gly Cys Lys 85 90 95 Leu Leu Ala Phe Leu AlaAla Leu Phe Cys Phe His Ala Ala Phe Leu 100 105 110 Leu Leu Gly Val GlyVal Thr Arg Tyr Leu Ala Ile Ala His His Arg 115 120 125 Phe Tyr Ala GluArg Leu Ala Gly Trp Pro Cys Ala Ala Met Leu Val 130 135 140 Cys Ala AlaTrp Ala Leu Ala Leu Ala Ala Ala Phe Pro Pro Val Leu 145 150 155 160 AspGly Gly Gly Asp Asp Glu Asp Ala Pro Cys Ala Leu Glu Gln Arg 165 170 175Pro Asp Gly Ala Pro Gly Ala Leu Gly Phe Leu Leu Leu Leu Ala Val 180 185190 Val Val Gly Ala Thr His Leu Val Tyr Leu Arg Leu Leu Phe Phe Ile 195200 205 His Asp Arg Arg Lys Met Arg Pro Ala Arg Leu Val Pro Ala Val Ser210 215 220 His Asp Trp Thr Phe His Gly Pro Gly Ala Thr Gly Gln Ala AlaAla 225 230 235 240 Asn Trp Thr Ala Gly Phe Gly Arg Gly Pro Thr Pro ProAla Leu Val 245 250 255 Gly Ile Arg Pro Ala Gly Pro Gly Arg Gly Ala ArgArg Leu Leu Val 260 265 270 Leu Glu Glu Phe Lys Thr Glu Lys Arg Leu CysLys Met Phe Tyr Ala 275 280 285 Val Thr Leu Leu Phe Leu Leu Leu Trp GlyPro Tyr Val Val Ala Ser 290 295 300 Tyr Leu Arg Val Leu Val Arg Pro GlyAla Val Pro Gln Ala Tyr Leu 305 310 315 320 Thr Ala Ser Val Trp Leu ThrPhe Ala Gln Ala Gly Ile Asn Pro Val 325 330 335 Val Cys Phe Leu Phe AsnArg Glu Leu Arg Asp Cys Phe Arg Ala Gln 340 345 350 Phe Pro Cys Cys GlnSer Pro Arg Thr Thr Gln Ala Thr His Pro Cys 355 360 365 Asp Leu Lys GlyIle Gly Leu 370 375 17 1002 DNA Homo sapiens 17 atgaacacca cagtgatgcaaggcttcaac agatctgagc ggtgccccag agacactcgg 60 atagtacagc tggtattcccagccctctac acagtggttt tcttgaccgg catcctgctg 120 aatactttgg ctctgtgggtgtttgttcac atccccagct cctccacctt catcatctac 180 ctcaaaaaca ctttggtggccgacttgata atgacactca tgcttccttt caaaatcctc 240 tctgactcac acctggcaccctggcagctc agagcttttg tgtgtcgttt ttcttcggtg 300 atattttatg agaccatgtatgtgggcatc gtgctgttag ggctcatagc ctttgacaga 360 ttcctcaaga tcatcagacctttgagaaat atttttctaa aaaaacctgt ttttgcaaaa 420 acggtctcaa tcttcatctggttctttttg ttcttcatct ccctgccaaa tacgatcttg 480 agcaacaagg aagcaacaccatcgtctgtg aaaaagtgtg cttccttaaa ggggcctctg 540 gggctgaaat ggcatcaaatggtaaataac atatgccagt ttattttctg gactgttttt 600 atcctaatgc ttgtgttttatgtggttatt gcaaaaaaag tatatgattc ttatagaaag 660 tccaaaagta aggacagaaaaaacaacaaa aagctggaag gcaaagtatt tgttgtcgtg 720 gctgtcttct ttgtgtgttttgctccattt cattttgcca gagttccata tactcacagt 780 caaaccaaca ataagactgactgtagactg caaaatcaac tgtttattgc taaagaaaca 840 actctctttt tggcagcaactaacatttgt atggatccct taatatacat attcttatgt 900 aaaaaattca cagaaaagctaccatgtatg caagggagaa agaccacagc atcaagccaa 960 gaaaatcata gcagtcagacagacaacata accttaggct ga 1002 18 333 PRT Homo sapiens 18 Met Asn Thr ThrVal Met Gln Gly Phe Asn Arg Ser Glu Arg Cys Pro 1 5 10 15 Arg Asp ThrArg Ile Val Gln Leu Val Phe Pro Ala Leu Tyr Thr Val 20 25 30 Val Phe LeuThr Gly Ile Leu Leu Asn Thr Leu Ala Leu Trp Val Phe 35 40 45 Val His IlePro Ser Ser Ser Thr Phe Ile Ile Tyr Leu Lys Asn Thr 50 55 60 Leu Val AlaAsp Leu Ile Met Thr Leu Met Leu Pro Phe Lys Ile Leu 65 70 75 80 Ser AspSer His Leu Ala Pro Trp Gln Leu Arg Ala Phe Val Cys Arg 85 90 95 Phe SerSer Val Ile Phe Tyr Glu Thr Met Tyr Val Gly Ile Val Leu 100 105 110 LeuGly Leu Ile Ala Phe Asp Arg Phe Leu Lys Ile Ile Arg Pro Leu 115 120 125Arg Asn Ile Phe Leu Lys Lys Pro Val Phe Ala Lys Thr Val Ser Ile 130 135140 Phe Ile Trp Phe Phe Leu Phe Phe Ile Ser Leu Pro Asn Thr Ile Leu 145150 155 160 Ser Asn Lys Glu Ala Thr Pro Ser Ser Val Lys Lys Cys Ala SerLeu 165 170 175 Lys Gly Pro Leu Gly Leu Lys Trp His Gln Met Val Asn AsnIle Cys 180 185 190 Gln Phe Ile Phe Trp Thr Val Phe Ile Leu Met Leu ValPhe Tyr Val 195 200 205 Val Ile Ala Lys Lys Val Tyr Asp Ser Tyr Arg LysSer Lys Ser Lys 210 215 220 Asp Arg Lys Asn Asn Lys Lys Leu Glu Gly LysVal Phe Val Val Val 225 230 235 240 Ala Val Phe Phe Val Cys Phe Ala ProPhe His Phe Ala Arg Val Pro 245 250 255 Tyr Thr His Ser Gln Thr Asn AsnLys Thr Asp Cys Arg Leu Gln Asn 260 265 270 Gln Leu Phe Ile Ala Lys GluThr Thr Leu Phe Leu Ala Ala Thr Asn 275 280 285 Ile Cys Met Asp Pro LeuIle Tyr Ile Phe Leu Cys Lys Lys Phe Thr 290 295 300 Glu Lys Leu Pro CysMet Gln Gly Arg Lys Thr Thr Ala Ser Ser Gln 305 310 315 320 Glu Asn HisSer Ser Gln Thr Asp Asn Ile Thr Leu Gly 325 330 19 1122 DNA Homo sapiens19 atggccaaca ctaccggaga gcctgaggag gtgagcggcg ctctgtcccc accgtccgca 60tcagcttatg tgaagctggt actgctggga ctgattatgt gcgtgagcct ggcgggtaac 120gccatcttgt ccctgctggt gctcaaggag cgtgccctgc acaaggctcc ttactacttc 180ctgctggacc tgtgcctggc cgatggcata cgctctgccg tctgcttccc ctttgtgctg 240gcttctgtgc gccacggctc ttcatggacc ttcagtgcac tcagctgcaa gattgtggcc 300tttatggccg tgctcttttg cttccatgcg gccttcatgc tgttctgcat cagcgtcacc 360cgctacatgg ccatcgccca ccaccgcttc tacgccaagc gcatgacact ctggacatgc 420gcggctgtca tctgcatggc ctggaccctg tctgtggcca tggccttccc acctgtcttt 480gacgtgggca cctacaagtt tattcgggag gaggaccagt gcatctttga gcatcgctac 540ttcaaggcca atgacacgct gggcttcatg cttatgttgg ctgtgctcat ggcagctacc 600catgctgtct acggcaagct gctcctcttc gagtatcgtc accgcaagat gaagccagtg 660cagatggtgc cagccatcag ccagaactgg acattccatg gtcccggggc caccggccag 720gctgctgcca actggatcgc cggctttggc cgtgggccca tgccaccaac cctgctgggt 780atccggcaga atgggcatgc agccagccgg cggctactgg gcatggacga ggtcaagggt 840gaaaagcagc tgggccgcat gttctacgcg atcacactgc tctttctgct cctctggtca 900ccctacatcg tggcctgcta ctggcgagtg tttgtgaaag cctgtgctgt gccccaccgc 960tacctggcca ctgctgtttg gatgagcttc gcccaggctg ccgtcaaccc aattgtctgc 1020ttcctgctca acaaggacct caagaagtgc ctgaccactc acgccccctg ctggggcaca 1080ggaggtgccc cggctcccag agaaccctac tgtgtcatgt ga 1122 20 373 PRT Homosapiens 20 Met Ala Asn Thr Thr Gly Glu Pro Glu Glu Val Ser Gly Ala LeuSer 1 5 10 15 Pro Pro Ser Ala Ser Ala Tyr Val Lys Leu Val Leu Leu GlyLeu Ile 20 25 30 Met Cys Val Ser Leu Ala Gly Asn Ala Ile Leu Ser Leu LeuVal Leu 35 40 45 Lys Glu Arg Ala Leu His Lys Ala Pro Tyr Tyr Phe Leu LeuAsp Leu 50 55 60 Cys Leu Ala Asp Gly Ile Arg Ser Ala Val Cys Phe Pro PheVal Leu 65 70 75 80 Ala Ser Val Arg His Gly Ser Ser Trp Thr Phe Ser AlaLeu Ser Cys 85 90 95 Lys Ile Val Ala Phe Met Ala Val Leu Phe Cys Phe HisAla Ala Phe 100 105 110 Met Leu Phe Cys Ile Ser Val Thr Arg Tyr Met AlaIle Ala His His 115 120 125 Arg Phe Tyr Ala Lys Arg Met Thr Leu Trp ThrCys Ala Ala Val Ile 130 135 140 Cys Met Ala Trp Thr Leu Ser Val Ala MetAla Phe Pro Pro Val Phe 145 150 155 160 Asp Val Gly Thr Tyr Lys Phe IleArg Glu Glu Asp Gln Cys Ile Phe 165 170 175 Glu His Arg Tyr Phe Lys AlaAsn Asp Thr Leu Gly Phe Met Leu Met 180 185 190 Leu Ala Val Leu Met AlaAla Thr His Ala Val Tyr Gly Lys Leu Leu 195 200 205 Leu Phe Glu Tyr ArgHis Arg Lys Met Lys Pro Val Gln Met Val Pro 210 215 220 Ala Ile Ser GlnAsn Trp Thr Phe His Gly Pro Gly Ala Thr Gly Gln 225 230 235 240 Ala AlaAla Asn Trp Ile Ala Gly Phe Gly Arg Gly Pro Met Pro Pro 245 250 255 ThrLeu Leu Gly Ile Arg Gln Asn Gly His Ala Ala Ser Arg Arg Leu 260 265 270Leu Gly Met Asp Glu Val Lys Gly Glu Lys Gln Leu Gly Arg Met Phe 275 280285 Tyr Ala Ile Thr Leu Leu Phe Leu Leu Leu Trp Ser Pro Tyr Ile Val 290295 300 Ala Cys Tyr Trp Arg Val Phe Val Lys Ala Cys Ala Val Pro His Arg305 310 315 320 Tyr Leu Ala Thr Ala Val Trp Met Ser Phe Ala Gln Ala AlaVal Asn 325 330 335 Pro Ile Val Cys Phe Leu Leu Asn Lys Asp Leu Lys LysCys Leu Thr 340 345 350 Thr His Ala Pro Cys Trp Gly Thr Gly Gly Ala ProAla Pro Arg Glu 355 360 365 Pro Tyr Cys Val Met 370 21 1053 DNA Homosapiens 21 atggctttgg aacagaacca gtcaacagat tattattatg aggaaaatgaaatgaatggc 60 acttatgact acagtcaata tgaattgatc tgtatcaaag aagatgtcagagaatttgca 120 aaagttttcc tccctgtatt cctcacaata gctttcgtca ttggacttgcaggcaattcc 180 atggtagtgg caatttatgc ctattacaag aaacagagaa ccaaaacagatgtgtacatc 240 ctgaatttgg ctgtagcaga tttactcctt ctattcactc tgcctttttgggctgttaat 300 gcagttcatg ggtgggtttt agggaaaata atgtgcaaaa taacttcagccttgtacaca 360 ctaaactttg tctctggaat gcagtttctg gcttgcatca gcatagacagatatgtggca 420 gtaactaatg tccccagcca atcaggagtg ggaaaaccat gctggatcatctgtttctgt 480 gtctggatgg ctgccatctt gctgagcata ccccagctgg ttttttatacagtaaatgac 540 aatgctaggt gcattcccat tttcccccgc tacctaggaa catcaatgaaagcattgatt 600 caaatgctag agatctgcat tggatttgta gtaccctttc ttattatgggggtgtgctac 660 tttatcacgg caaggacact catgaagatg ccaaacatta aaatatctcgacccctaaaa 720 gttctgctca cagtcgttat agttttcatt gtcactcaac tgccttataacattgtcaag 780 ttctgccgag ccatagacat catctactcc ctgatcacca gctgcaacatgagcaaacgc 840 atggacatcg ccatccaagt cacagaaagc attgcactct ttcacagctgcctcaaccca 900 atcctttatg tttttatggg agcatctttc aaaaactacg ttatgaaagtggccaagaaa 960 tatgggtcct ggagaagaca gagacaaagt gtggaggagt ttccttttgattctgagggt 1020 cctacagagc caaccagtac ttttagcatt taa 1053 22 350 PRTHomo sapiens 22 Met Ala Leu Glu Gln Asn Gln Ser Thr Asp Tyr Tyr Tyr GluGlu Asn 1 5 10 15 Glu Met Asn Gly Thr Tyr Asp Tyr Ser Gln Tyr Glu LeuIle Cys Ile 20 25 30 Lys Glu Asp Val Arg Glu Phe Ala Lys Val Phe Leu ProVal Phe Leu 35 40 45 Thr Ile Ala Phe Val Ile Gly Leu Ala Gly Asn Ser MetVal Val Ala 50 55 60 Ile Tyr Ala Tyr Tyr Lys Lys Gln Arg Thr Lys Thr AspVal Tyr Ile 65 70 75 80 Leu Asn Leu Ala Val Ala Asp Leu Leu Leu Leu PheThr Leu Pro Phe 85 90 95 Trp Ala Val Asn Ala Val His Gly Trp Val Leu GlyLys Ile Met Cys 100 105 110 Lys Ile Thr Ser Ala Leu Tyr Thr Leu Asn PheVal Ser Gly Met Gln 115 120 125 Phe Leu Ala Cys Ile Ser Ile Asp Arg TyrVal Ala Val Thr Asn Val 130 135 140 Pro Ser Gln Ser Gly Val Gly Lys ProCys Trp Ile Ile Cys Phe Cys 145 150 155 160 Val Trp Met Ala Ala Ile LeuLeu Ser Ile Pro Gln Leu Val Phe Tyr 165 170 175 Thr Val Asn Asp Asn AlaArg Cys Ile Pro Ile Phe Pro Arg Tyr Leu 180 185 190 Gly Thr Ser Met LysAla Leu Ile Gln Met Leu Glu Ile Cys Ile Gly 195 200 205 Phe Val Val ProPhe Leu Ile Met Gly Val Cys Tyr Phe Ile Thr Ala 210 215 220 Arg Thr LeuMet Lys Met Pro Asn Ile Lys Ile Ser Arg Pro Leu Lys 225 230 235 240 ValLeu Leu Thr Val Val Ile Val Phe Ile Val Thr Gln Leu Pro Tyr 245 250 255Asn Ile Val Lys Phe Cys Arg Ala Ile Asp Ile Ile Tyr Ser Leu Ile 260 265270 Thr Ser Cys Asn Met Ser Lys Arg Met Asp Ile Ala Ile Gln Val Thr 275280 285 Glu Ser Ile Ala Leu Phe His Ser Cys Leu Asn Pro Ile Leu Tyr Val290 295 300 Phe Met Gly Ala Ser Phe Lys Asn Tyr Val Met Lys Val Ala LysLys 305 310 315 320 Tyr Gly Ser Trp Arg Arg Gln Arg Gln Ser Val Glu GluPhe Pro Phe 325 330 335 Asp Ser Glu Gly Pro Thr Glu Pro Thr Ser Thr PheSer Ile 340 345 350 23 1116 DNA Homo sapiens 23 atgccaggaa acgccaccccagtgaccacc actgccccgt gggcctccct gggcctctcc 60 gccaagacct gcaacaacgtgtccttcgaa gagagcagga tagtcctggt cgtggtgtac 120 agcgcggtgt gcacgctgggggtgccggcc aactgcctga ctgcgtggct ggcgctgctg 180 caggtactgc agggcaacgtgctggccgtc tacctgctct gcctggcact ctgcgaactg 240 ctgtacacag gcacgctgccactctgggtc atctatatcc gcaaccagca ccgctggacc 300 ctaggcctgc tggcctcgaaggtgaccgcc tacatcttct tctgcaacat ctacgtcagc 360 atcctcttcc tgtgctgcatctcctgcgac cgcttcgtgg ccgtggtgta cgcgctggag 420 agtcggggcc gccgccgccggaggaccgcc atcctcatct ccgcctgcat cttcatcctc 480 gtcgggatcg ttcactacccggtgttccag acggaagaca aggagacctg ctttgacatg 540 ctgcagatgg acagcaggattgccgggtac tactacgcca ggttcaccgt tggctttgcc 600 atccctctct ccatcatcgccttcaccaac caccggattt tcaggagcat caagcagagc 660 atgggcttaa gcgctgcccagaaggccaag gtgaagcact cggccatcgc ggtggttgtc 720 atcttcctag tctgcttcgccccgtaccac ctggttctcc tcgtcaaagc cgctgccttt 780 tcctactaca gaggagacaggaacgccatg tgcggcttgg aggaaaggct gtacacagcc 840 tctgtggtgt ttctgtgcctgtccacggtg aacggcgtgg ctgaccccat tatctacgtg 900 ctggccacgg accattcccgccaagaagtg tccagaatcc ataaggggtg gaaagagtgg 960 tccatgaaga cagacgtcaccaggctcacc cacagcaggg acaccgagga gctgcagtcg 1020 cccgtggccc ttgcagaccactacaccttc tccaggcccg tgcacccacc agggtcacca 1080 tgccctgcaa agaggctgattgaggagtcc tgctga 1116 24 371 PRT Homo sapiens 24 Met Pro Gly Asn AlaThr Pro Val Thr Thr Thr Ala Pro Trp Ala Ser 1 5 10 15 Leu Gly Leu SerAla Lys Thr Cys Asn Asn Val Ser Phe Glu Glu Ser 20 25 30 Arg Ile Val LeuVal Val Val Tyr Ser Ala Val Cys Thr Leu Gly Val 35 40 45 Pro Ala Asn CysLeu Thr Ala Trp Leu Ala Leu Leu Gln Val Leu Gln 50 55 60 Gly Asn Val LeuAla Val Tyr Leu Leu Cys Leu Ala Leu Cys Glu Leu 65 70 75 80 Leu Tyr ThrGly Thr Leu Pro Leu Trp Val Ile Tyr Ile Arg Asn Gln 85 90 95 His Arg TrpThr Leu Gly Leu Leu Ala Ser Lys Val Thr Ala Tyr Ile 100 105 110 Phe PheCys Asn Ile Tyr Val Ser Ile Leu Phe Leu Cys Cys Ile Ser 115 120 125 CysAsp Arg Phe Val Ala Val Val Tyr Ala Leu Glu Ser Arg Gly Arg 130 135 140Arg Arg Arg Arg Thr Ala Ile Leu Ile Ser Ala Cys Ile Phe Ile Leu 145 150155 160 Val Gly Ile Val His Tyr Pro Val Phe Gln Thr Glu Asp Lys Glu Thr165 170 175 Cys Phe Asp Met Leu Gln Met Asp Ser Arg Ile Ala Gly Tyr TyrTyr 180 185 190 Ala Arg Phe Thr Val Gly Phe Ala Ile Pro Leu Ser Ile IleAla Phe 195 200 205 Thr Asn His Arg Ile Phe Arg Ser Ile Lys Gln Ser MetGly Leu Ser 210 215 220 Ala Ala Gln Lys Ala Lys Val Lys His Ser Ala IleAla Val Val Val 225 230 235 240 Ile Phe Leu Val Cys Phe Ala Pro Tyr HisLeu Val Leu Leu Val Lys 245 250 255 Ala Ala Ala Phe Ser Tyr Tyr Arg GlyAsp Arg Asn Ala Met Cys Gly 260 265 270 Leu Glu Glu Arg Leu Tyr Thr AlaSer Val Val Phe Leu Cys Leu Ser 275 280 285 Thr Val Asn Gly Val Ala AspPro Ile Ile Tyr Val Leu Ala Thr Asp 290 295 300 His Ser Arg Gln Glu ValSer Arg Ile His Lys Gly Trp Lys Glu Trp 305 310 315 320 Ser Met Lys ThrAsp Val Thr Arg Leu Thr His Ser Arg Asp Thr Glu 325 330 335 Glu Leu GlnSer Pro Val Ala Leu Ala Asp His Tyr Thr Phe Ser Arg 340 345 350 Pro ValHis Pro Pro Gly Ser Pro Cys Pro Ala Lys Arg Leu Ile Glu 355 360 365 GluSer Cys 370 25 1113 DNA Homo sapiens 25 atggcgaact atagccatgc agctgacaacattttgcaaa atctctcgcc tctaacagcc 60 tttctgaaac tgacttcctt gggtttcataataggagtca gcgtggtggg caacctcctg 120 atctccattt tgctagtgaa agataagaccttgcatagag caccttacta cttcctgttg 180 gatctttgct gttcagatat cctcagatctgcaatttgtt tcccatttgt gttcaactct 240 gtcaaaaatg gctctacctg gacttatgggactctgactt gcaaagtgat tgcctttctg 300 ggggttttgt cctgtttcca cactgctttcatgctcttct gcatcagtgt caccagatac 360 ttagctatcg cccatcaccg cttctatacaaagaggctga ccttttggac gtgtctggct 420 gtgatctgta tggtgtggac tctgtctgtggccatggcat ttcccccggt tttagacgtg 480 ggcacttact cattcattag ggaggaagatcaatgcacct tccaacaccg ctccttcagg 540 gctaatgatt ccttaggatt tatgctgcttcttgctctca tcctcctagc cacacagctt 600 gtctacctca agctgatatt tttcgtccacgatcgaagaa aaatgaagcc agtccagttt 660 gtagcagcag tcagccagaa ctggacttttcatggtcctg gagccagtgg ccaggcagct 720 gccaattggc tagcaggatt tggaaggggtcccacaccac ccaccttgct gggcatcagg 780 caaaatgcaa acaccacagg cagaagaaggctattggtct tagacgagtt caaaatggag 840 aaaagaatca gcagaatgtt ctatataatgacttttctgt ttctaacctt gtggggcccc 900 tacctggtgg cctgttattg gagagtttttgcaagagggc ctgtagtacc agggggattt 960 ctaacagctg ctgtctggat gagttttgcccaagcaggaa tcaatccttt tgtctgcatt 1020 ttctcaaaca gggagctgag gcgctgtttcagcacaaccc ttctttactg cagaaaatcc 1080 aggttaccaa gggaacctta ctgtgttatatga 1113 26 370 PRT Homo sapiens 26 Met Ala Asn Tyr Ser His Ala Ala AspAsn Ile Leu Gln Asn Leu Ser 1 5 10 15 Pro Leu Thr Ala Phe Leu Lys LeuThr Ser Leu Gly Phe Ile Ile Gly 20 25 30 Val Ser Val Val Gly Asn Leu LeuIle Ser Ile Leu Leu Val Lys Asp 35 40 45 Lys Thr Leu His Arg Ala Pro TyrTyr Phe Leu Leu Asp Leu Cys Cys 50 55 60 Ser Asp Ile Leu Arg Ser Ala IleCys Phe Pro Phe Val Phe Asn Ser 65 70 75 80 Val Lys Asn Gly Ser Thr TrpThr Tyr Gly Thr Leu Thr Cys Lys Val 85 90 95 Ile Ala Phe Leu Gly Val LeuSer Cys Phe His Thr Ala Phe Met Leu 100 105 110 Phe Cys Ile Ser Val ThrArg Tyr Leu Ala Ile Ala His His Arg Phe 115 120 125 Tyr Thr Lys Arg LeuThr Phe Trp Thr Cys Leu Ala Val Ile Cys Met 130 135 140 Val Trp Thr LeuSer Val Ala Met Ala Phe Pro Pro Val Leu Asp Val 145 150 155 160 Gly ThrTyr Ser Phe Ile Arg Glu Glu Asp Gln Cys Thr Phe Gln His 165 170 175 ArgSer Phe Arg Ala Asn Asp Ser Leu Gly Phe Met Leu Leu Leu Ala 180 185 190Leu Ile Leu Leu Ala Thr Gln Leu Val Tyr Leu Lys Leu Ile Phe Phe 195 200205 Val His Asp Arg Arg Lys Met Lys Pro Val Gln Phe Val Ala Ala Val 210215 220 Ser Gln Asn Trp Thr Phe His Gly Pro Gly Ala Ser Gly Gln Ala Ala225 230 235 240 Ala Asn Trp Leu Ala Gly Phe Gly Arg Gly Pro Thr Pro ProThr Leu 245 250 255 Leu Gly Ile Arg Gln Asn Ala Asn Thr Thr Gly Arg ArgArg Leu Leu 260 265 270 Val Leu Asp Glu Phe Lys Met Glu Lys Arg Ile SerArg Met Phe Tyr 275 280 285 Ile Met Thr Phe Leu Phe Leu Thr Leu Trp GlyPro Tyr Leu Val Ala 290 295 300 Cys Tyr Trp Arg Val Phe Ala Arg Gly ProVal Val Pro Gly Gly Phe 305 310 315 320 Leu Thr Ala Ala Val Trp Met SerPhe Ala Gln Ala Gly Ile Asn Pro 325 330 335 Phe Val Cys Ile Phe Ser AsnArg Glu Leu Arg Arg Cys Phe Ser Thr 340 345 350 Thr Leu Leu Tyr Cys ArgLys Ser Arg Leu Pro Arg Glu Pro Tyr Cys 355 360 365 Val Ile 370 27 1080DNA Homo sapiens 27 atgcaggtcc cgaacagcac cggcccggac aacgcgacgctgcagatgct gcggaacccg 60 gcgatcgcgg tggccctgcc cgtggtgtac tcgctggtggcggcggtcag catcccgggc 120 aacctcttct ctctgtgggt gctgtgccgg cgcatggggcccagatcccc gtcggtcatc 180 ttcatgatca acctgagcgt cacggacctg atgctggccagcgtgttgcc tttccaaatc 240 tactaccatt gcaaccgcca ccactgggta ttcggggtgctgctttgcaa cgtggtgacc 300 gtggcctttt acgcaaacat gtattccagc atcctcaccatgacctgtat cagcgtggag 360 cgcttcctgg gggtcctgta cccgctcagc tccaagcgctggcgccgccg tcgttacgcg 420 gtggccgcgt gtgcagggac ctggctgctg ctcctgaccgccctgtgccc gctggcgcgc 480 accgatctca cctacccggt gcacgccctg ggcatcatcacctgcttcga cgtcctcaag 540 tggacgatgc tccccagcgt ggccatgtgg gccgtgttcctcttcaccat cttcatcctg 600 ctgttcctca tcccgttcgt gatcaccgtg gcttgttacacggccaccat cctcaagctg 660 ttgcgcacgg aggaggcgca cggccgggag cagcggaggcgcgcggtggg cctggccgcg 720 gtggtcttgc tggcctttgt cacctgcttc gcccccaacaacttcgtgct cctggcgcac 780 atcgtgagcc gcctgttcta cggcaagagc tactaccacgtgtacaagct cacgctgtgt 840 ctcagctgcc tcaacaactg tctggacccg tttgtttattactttgcgtc ccgggaattc 900 cagctgcgcc tgcgggaata tttgggctgc cgccgggtgcccagagacac cctggacacg 960 cgccgcgaga gcctcttctc cgccaggacc acgtccgtgcgctccgaggc cggtgcgcac 1020 cctgaaggga tggagggagc caccaggccc ggcctccagaggcaggagag tgtgttctga 1080 28 359 PRT Homo sapiens 28 Met Gln Val ProAsn Ser Thr Gly Pro Asp Asn Ala Thr Leu Gln Met 1 5 10 15 Leu Arg AsnPro Ala Ile Ala Val Ala Leu Pro Val Val Tyr Ser Leu 20 25 30 Val Ala AlaVal Ser Ile Pro Gly Asn Leu Phe Ser Leu Trp Val Leu 35 40 45 Cys Arg ArgMet Gly Pro Arg Ser Pro Ser Val Ile Phe Met Ile Asn 50 55 60 Leu Ser ValThr Asp Leu Met Leu Ala Ser Val Leu Pro Phe Gln Ile 65 70 75 80 Tyr TyrHis Cys Asn Arg His His Trp Val Phe Gly Val Leu Leu Cys 85 90 95 Asn ValVal Thr Val Ala Phe Tyr Ala Asn Met Tyr Ser Ser Ile Leu 100 105 110 ThrMet Thr Cys Ile Ser Val Glu Arg Phe Leu Gly Val Leu Tyr Pro 115 120 125Leu Ser Ser Lys Arg Trp Arg Arg Arg Arg Tyr Ala Val Ala Ala Cys 130 135140 Ala Gly Thr Trp Leu Leu Leu Leu Thr Ala Leu Cys Pro Leu Ala Arg 145150 155 160 Thr Asp Leu Thr Tyr Pro Val His Ala Leu Gly Ile Ile Thr CysPhe 165 170 175 Asp Val Leu Lys Trp Thr Met Leu Pro Ser Val Ala Met TrpAla Val 180 185 190 Phe Leu Phe Thr Ile Phe Ile Leu Leu Phe Leu Ile ProPhe Val Ile 195 200 205 Thr Val Ala Cys Tyr Thr Ala Thr Ile Leu Lys LeuLeu Arg Thr Glu 210 215 220 Glu Ala His Gly Arg Glu Gln Arg Arg Arg AlaVal Gly Leu Ala Ala 225 230 235 240 Val Val Leu Leu Ala Phe Val Thr CysPhe Ala Pro Asn Asn Phe Val 245 250 255 Leu Leu Ala His Ile Val Ser ArgLeu Phe Tyr Gly Lys Ser Tyr Tyr 260 265 270 His Val Tyr Lys Leu Thr LeuCys Leu Ser Cys Leu Asn Asn Cys Leu 275 280 285 Asp Pro Phe Val Tyr TyrPhe Ala Ser Arg Glu Phe Gln Leu Arg Leu 290 295 300 Arg Glu Tyr Leu GlyCys Arg Arg Val Pro Arg Asp Thr Leu Asp Thr 305 310 315 320 Arg Arg GluSer Leu Phe Ser Ala Arg Thr Thr Ser Val Arg Ser Glu 325 330 335 Ala GlyAla His Pro Glu Gly Met Glu Gly Ala Thr Arg Pro Gly Leu 340 345 350 GlnArg Gln Glu Ser Val Phe 355 29 1503 DNA Homo sapiens 29 atggagcgtccctgggagga cagcccaggc ccggaggggg cagctgaggg ctcgcctgtg 60 ccagtcgccgccggggcgcg ctccggtgcc gcggcgagtg gcacaggctg gcagccatgg 120 gctgagtgcccgggacccaa ggggaggggg caactgctgg cgaccgccgg ccctttgcgt 180 cgctggcccgccccctcgcc tgccagctcc agccccgccc ccggagcggc gtccgctcac 240 tcggttcaaggcagcgcgac tgcgggtggc gcacgaccag ggcgcagacc ttggggcgcg 300 cggcccatggagtcggggct gctgcggccg gcgccggtga gcgaggtcat cgtcctgcat 360 tacaactacaccggcaagct ccgcggtgcg agctaccagc cgggtgccgg cctgcgcgcc 420 gacgccgtggtgtgcctggc ggtgtgcgcc ttcatcgtgc tagagaatct agccgtgttg 480 ttggtgctcggacgccaccc gcgcttccac gctcccatgt tcctgctcct gggcagcctc 540 acgttgtcggatctgctggc aggcgccgcc tacgccgcca acatcctact gtcggggccg 600 ctcacgctgaaactgtcccc cgcgctctgg ttcgcacggg agggaggcgt cttcgtggca 660 ctcactgcgtccgtgctgag cctcctggcc atcgcgctgg agcgcagcct caccatggcg 720 cgcagggggcccgcgcccgt ctccagtcgg gggcgcacgc tggcgatggc agccgcggcc 780 tggggcgtgtcgctgctcct cgggctcctg ccagcgctgg gctggaattg cctgggtcgc 840 ctggacgcttgctccactgt cttgccgctc tacgccaagg cctacgtgct cttctgcgtg 900 ctcgccttcgtgggcatcct ggccgcgatc tgtgcactct acgcgcgcat ctactgccag 960 gtacgcgccaacgcgcggcg cctgccggca cggcccggga ctgcggggac cacctcgacc 1020 cgggcgcgtcgcaagccgcg ctctctggcc ttgctgcgca cgctcagcgt ggtgctcctg 1080 gcctttgtggcatgttgggg ccccctcttc ctgctgctgt tgctcgacgt ggcgtgcccg 1140 gcgcgcacctgtcctgtact cctgcaggcc gatcccttcc tgggactggc catggccaac 1200 tcacttctgaaccccatcat ctacacgctc accaaccgcg acctgcgcca cgcgctcctg 1260 cgcctggtctgctgcggacg ccactcctgc ggcagagacc cgagtggctc ccagcagtcg 1320 gcgagcgcggctgaggcttc cgggggcctg cgccgctgcc tgcccccggg ccttgatggg 1380 agcttcagcggctcggagcg ctcatcgccc cagcgcgacg ggctggacac cagcggctcc 1440 acaggcagccccggtgcacc cacagccgcc cggactctgg tatcagaacc ggctgcagac 1500 tga 1503 30500 PRT Homo sapiens 30 Met Glu Arg Pro Trp Glu Asp Ser Pro Gly Pro GluGly Ala Ala Glu 1 5 10 15 Gly Ser Pro Val Pro Val Ala Ala Gly Ala ArgSer Gly Ala Ala Ala 20 25 30 Ser Gly Thr Gly Trp Gln Pro Trp Ala Glu CysPro Gly Pro Lys Gly 35 40 45 Arg Gly Gln Leu Leu Ala Thr Ala Gly Pro LeuArg Arg Trp Pro Ala 50 55 60 Pro Ser Pro Ala Ser Ser Ser Pro Ala Pro GlyAla Ala Ser Ala His 65 70 75 80 Ser Val Gln Gly Ser Ala Thr Ala Gly GlyAla Arg Pro Gly Arg Arg 85 90 95 Pro Trp Gly Ala Arg Pro Met Glu Ser GlyLeu Leu Arg Pro Ala Pro 100 105 110 Val Ser Glu Val Ile Val Leu His TyrAsn Tyr Thr Gly Lys Leu Arg 115 120 125 Gly Ala Ser Tyr Gln Pro Gly AlaGly Leu Arg Ala Asp Ala Val Val 130 135 140 Cys Leu Ala Val Cys Ala PheIle Val Leu Glu Asn Leu Ala Val Leu 145 150 155 160 Leu Val Leu Gly ArgHis Pro Arg Phe His Ala Pro Met Phe Leu Leu 165 170 175 Leu Gly Ser LeuThr Leu Ser Asp Leu Leu Ala Gly Ala Ala Tyr Ala 180 185 190 Ala Asn IleLeu Leu Ser Gly Pro Leu Thr Leu Lys Leu Ser Pro Ala 195 200 205 Leu TrpPhe Ala Arg Glu Gly Gly Val Phe Val Ala Leu Thr Ala Ser 210 215 220 ValLeu Ser Leu Leu Ala Ile Ala Leu Glu Arg Ser Leu Thr Met Ala 225 230 235240 Arg Arg Gly Pro Ala Pro Val Ser Ser Arg Gly Arg Thr Leu Ala Met 245250 255 Ala Ala Ala Ala Trp Gly Val Ser Leu Leu Leu Gly Leu Leu Pro Ala260 265 270 Leu Gly Trp Asn Cys Leu Gly Arg Leu Asp Ala Cys Ser Thr ValLeu 275 280 285 Pro Leu Tyr Ala Lys Ala Tyr Val Leu Phe Cys Val Leu AlaPhe Val 290 295 300 Gly Ile Leu Ala Ala Ile Cys Ala Leu Tyr Ala Arg IleTyr Cys Gln 305 310 315 320 Val Arg Ala Asn Ala Arg Arg Leu Pro Ala ArgPro Gly Thr Ala Gly 325 330 335 Thr Thr Ser Thr Arg Ala Arg Arg Lys ProArg Ser Leu Ala Leu Leu 340 345 350 Arg Thr Leu Ser Val Val Leu Leu AlaPhe Val Ala Cys Trp Gly Pro 355 360 365 Leu Phe Leu Leu Leu Leu Leu AspVal Ala Cys Pro Ala Arg Thr Cys 370 375 380 Pro Val Leu Leu Gln Ala AspPro Phe Leu Gly Leu Ala Met Ala Asn 385 390 395 400 Ser Leu Leu Asn ProIle Ile Tyr Thr Leu Thr Asn Arg Asp Leu Arg 405 410 415 His Ala Leu LeuArg Leu Val Cys Cys Gly Arg His Ser Cys Gly Arg 420 425 430 Asp Pro SerGly Ser Gln Gln Ser Ala Ser Ala Ala Glu Ala Ser Gly 435 440 445 Gly LeuArg Arg Cys Leu Pro Pro Gly Leu Asp Gly Ser Phe Ser Gly 450 455 460 SerGlu Arg Ser Ser Pro Gln Arg Asp Gly Leu Asp Thr Ser Gly Ser 465 470 475480 Thr Gly Ser Pro Gly Ala Pro Thr Ala Ala Arg Thr Leu Val Ser Glu 485490 495 Pro Ala Ala Asp 500 31 1029 DNA Homo sapiens 31 atgcaagccgtcgacaatct cacctctgcg cctgggaaca ccagtctgtg caccagagac 60 tacaaaatcacccaggtcct cttcccactg ctctacactg tcctgttttt tgttggactt 120 atcacaaatggcctggcgat gaggattttc tttcaaatcc ggagtaaatc aaactttatt 180 atttttcttaagaacacagt catttctgat cttctcatga ttctgacttt tccattcaaa 240 attcttagtgatgccaaact gggaacagga ccactgagaa cttttgtgtg tcaagttacc 300 tccgtcatattttatttcac aatgtatatc agtatttcat tcctgggact gataactatc 360 gatcgctaccagaagaccac caggccattt aaaacatcca accccaaaaa tctcttgggg 420 gctaagattctctctgttgt catctgggca ttcatgttct tactctcttt gcctaacatg 480 attctgaccaacaggcagcc gagagacaag aatgtgaaga aatgctcttt ccttaaatca 540 gagttcggtctagtctggca tgaaatagta aattacatct gtcaagtcat tttctggatt 600 aatttcttaattgttattgt atgttataca ctcattacaa aagaactgta ccggtcatac 660 gtaagaacgaggggtgtagg taaagtcccc aggaaaaagg tgaacgtcaa agttttcatt 720 atcattgctgtattctttat ttgttttgtt cctttccatt ttgcccgaat tccttacacc 780 ctgagccaaacccgggatgt ctttgactgc actgctgaaa atactctgtt ctatgtgaaa 840 gagagcactctgtggttaac ttccttaaat gcatgcctgg atccgttcat ctattttttc 900 ctttgcaagtccttcagaaa ttccttgata agtatgctga agtgccccaa ttctgcaaca 960 tctctgtcccaggacaatag gaaaaaagaa caggatggtg gtgacccaaa tgaagagact 1020 ccaatgtaa1029 32 342 PRT Homo sapiens 32 Met Gln Ala Val Asp Asn Leu Thr Ser AlaPro Gly Asn Thr Ser Leu 1 5 10 15 Cys Thr Arg Asp Tyr Lys Ile Thr GlnVal Leu Phe Pro Leu Leu Tyr 20 25 30 Thr Val Leu Phe Phe Val Gly Leu IleThr Asn Gly Leu Ala Met Arg 35 40 45 Ile Phe Phe Gln Ile Arg Ser Lys SerAsn Phe Ile Ile Phe Leu Lys 50 55 60 Asn Thr Val Ile Ser Asp Leu Leu MetIle Leu Thr Phe Pro Phe Lys 65 70 75 80 Ile Leu Ser Asp Ala Lys Leu GlyThr Gly Pro Leu Arg Thr Phe Val 85 90 95 Cys Gln Val Thr Ser Val Ile PheTyr Phe Thr Met Tyr Ile Ser Ile 100 105 110 Ser Phe Leu Gly Leu Ile ThrIle Asp Arg Tyr Gln Lys Thr Thr Arg 115 120 125 Pro Phe Lys Thr Ser AsnPro Lys Asn Leu Leu Gly Ala Lys Ile Leu 130 135 140 Ser Val Val Ile TrpAla Phe Met Phe Leu Leu Ser Leu Pro Asn Met 145 150 155 160 Ile Leu ThrAsn Arg Gln Pro Arg Asp Lys Asn Val Lys Lys Cys Ser 165 170 175 Phe LeuLys Ser Glu Phe Gly Leu Val Trp His Glu Ile Val Asn Tyr 180 185 190 IleCys Gln Val Ile Phe Trp Ile Asn Phe Leu Ile Val Ile Val Cys 195 200 205Tyr Thr Leu Ile Thr Lys Glu Leu Tyr Arg Ser Tyr Val Arg Thr Arg 210 215220 Gly Val Gly Lys Val Pro Arg Lys Lys Val Asn Val Lys Val Phe Ile 225230 235 240 Ile Ile Ala Val Phe Phe Ile Cys Phe Val Pro Phe His Phe AlaArg 245 250 255 Ile Pro Tyr Thr Leu Ser Gln Thr Arg Asp Val Phe Asp CysThr Ala 260 265 270 Glu Asn Thr Leu Phe Tyr Val Lys Glu Ser Thr Leu TrpLeu Thr Ser 275 280 285 Leu Asn Ala Cys Leu Asp Pro Phe Ile Tyr Phe PheLeu Cys Lys Ser 290 295 300 Phe Arg Asn Ser Leu Ile Ser Met Leu Lys CysPro Asn Ser Ala Thr 305 310 315 320 Ser Leu Ser Gln Asp Asn Arg Lys LysGlu Gln Asp Gly Gly Asp Pro 325 330 335 Asn Glu Glu Thr Pro Met 340 331077 DNA Homo sapiens 33 atgtcggtct gctaccgtcc cccagggaac gagacactgctgagctggaa gacttcgcgg 60 gccacaggca cagccttcct gctgctggcg gcgctgctggggctgcctgg caacggcttc 120 gtggtgtgga gcttggcggg ctggcggcct gcacgggggcgaccgctggc ggccacgctt 180 gtgctgcacc tggcgctggc cgacggcgcg gtgctgctgctcacgccgct ctttgtggcc 240 ttcctgaccc ggcaggcctg gccgctgggc caggcgggctgcaaggcggt gtactacgtg 300 tgcgcgctca gcatgtacgc cagcgtgctg ctcaccggcctgctcagcct gcagcgctgc 360 ctcgcagtca cccgcccctt cctggcgcct cggctgcgcagcccggccct ggcccgccgc 420 ctgctgctgg cggtctggct ggccgccctg ttgctcgccgtcccggccgc cgtctaccgc 480 cacctgtgga gggaccgcgt atgccagctg tgccacccgtcgccggtcca cgccgccgcc 540 cacctgagcc tggagactct gaccgctttc gtgcttcctttcgggctgat gctcggctgc 600 tacagcgtga cgctggcacg gctgcggggc gcccgctggggctccgggcg gcacggggcg 660 cgggtgggcc ggctggtgag cgccatcgtg cttgccttcggcttgctctg ggccccctac 720 cacgcagtca accttctgca ggcggtcgca gcgctggctccaccggaagg ggccttggcg 780 aagctgggcg gagccggcca ggcggcgcga gcgggaactacggccttggc cttcttcagt 840 tctagcgtca acccggtgct ctacgtcttc accgctggagatctgctgcc ccgggcaggt 900 ccccgtttcc tcacgcggct cttcgaaggc tctggggaggcccgaggggg cggccgctct 960 agggaaggga ccatggagct ccgaactacc cctcagctgaaagtggtggg gcagggccgc 1020 ggcaatggag acccgggggg tgggatggag aaggacggtccggaatggga cctttga 1077 34 358 PRT Homo sapiens 34 Met Ser Val Cys TyrArg Pro Pro Gly Asn Glu Thr Leu Leu Ser Trp 1 5 10 15 Lys Thr Ser ArgAla Thr Gly Thr Ala Phe Leu Leu Leu Ala Ala Leu 20 25 30 Leu Gly Leu ProGly Asn Gly Phe Val Val Trp Ser Leu Ala Gly Trp 35 40 45 Arg Pro Ala ArgGly Arg Pro Leu Ala Ala Thr Leu Val Leu His Leu 50 55 60 Ala Leu Ala AspGly Ala Val Leu Leu Leu Thr Pro Leu Phe Val Ala 65 70 75 80 Phe Leu ThrArg Gln Ala Trp Pro Leu Gly Gln Ala Gly Cys Lys Ala 85 90 95 Val Tyr TyrVal Cys Ala Leu Ser Met Tyr Ala Ser Val Leu Leu Thr 100 105 110 Gly LeuLeu Ser Leu Gln Arg Cys Leu Ala Val Thr Arg Pro Phe Leu 115 120 125 AlaPro Arg Leu Arg Ser Pro Ala Leu Ala Arg Arg Leu Leu Leu Ala 130 135 140Val Trp Leu Ala Ala Leu Leu Leu Ala Val Pro Ala Ala Val Tyr Arg 145 150155 160 His Leu Trp Arg Asp Arg Val Cys Gln Leu Cys His Pro Ser Pro Val165 170 175 His Ala Ala Ala His Leu Ser Leu Glu Thr Leu Thr Ala Phe ValLeu 180 185 190 Pro Phe Gly Leu Met Leu Gly Cys Tyr Ser Val Thr Leu AlaArg Leu 195 200 205 Arg Gly Ala Arg Trp Gly Ser Gly Arg His Gly Ala ArgVal Gly Arg 210 215 220 Leu Val Ser Ala Ile Val Leu Ala Phe Gly Leu LeuTrp Ala Pro Tyr 225 230 235 240 His Ala Val Asn Leu Leu Gln Ala Val AlaAla Leu Ala Pro Pro Glu 245 250 255 Gly Ala Leu Ala Lys Leu Gly Gly AlaGly Gln Ala Ala Arg Ala Gly 260 265 270 Thr Thr Ala Leu Ala Phe Phe SerSer Ser Val Asn Pro Val Leu Tyr 275 280 285 Val Phe Thr Ala Gly Asp LeuLeu Pro Arg Ala Gly Pro Arg Phe Leu 290 295 300 Thr Arg Leu Phe Glu GlySer Gly Glu Ala Arg Gly Gly Gly Arg Ser 305 310 315 320 Arg Glu Gly ThrMet Glu Leu Arg Thr Thr Pro Gln Leu Lys Val Val 325 330 335 Gly Gln GlyArg Gly Asn Gly Asp Pro Gly Gly Gly Met Glu Lys Asp 340 345 350 Gly ProGlu Trp Asp Leu 355 35 1005 DNA Homo sapiens 35 atgctgggga tcatggcatggaatgcaact tgcaaaaact ggctggcagc agaggctgcc 60 ctggaaaagt actacctttccattttttat gggattgagt tcgttgtggg agtccttgga 120 aataccattg ttgtttacggctacatcttc tctctgaaga actggaacag cagtaatatt 180 tatctcttta acctctctgtctctgactta gcttttctgt gcaccctccc catgctgata 240 aggagttatg ccaatggaaactggatatat ggagacgtgc tctgcataag caaccgatat 300 gtgcttcatg ccaacctctataccagcatt ctctttctca cttttatcag catagatcga 360 tacttgataa ttaagtatcctttccgagaa caccttctgc aaaagaaaga gtttgctatt 420 ttaatctcct tggccatttgggttttagta accttagagt tactacccat acttcccctt 480 ataaatcctg ttataactgacaatggcacc acctgtaatg attttgcaag ttctggagac 540 cccaactaca acctcatttacagcatgtgt ctaacactgt tggggttcct tattcctctt 600 tttgtgatgt gtttcttttattacaagatt gctctcttcc taaagcagag gaataggcag 660 gttgctactg ctctgccccttgaaaagcct ctcaacttgg tcatcatggc agtggtaatc 720 ttctctgtgc tttttacaccctatcacgtc atgcggaatg tgaggatcgc ttcacgcctg 780 gggagttgga agcagtatcagtgcactcag gtcgtcatca actcctttta cattgtgaca 840 cggcctttgg cctttctgaacagtgtcatc aaccctgtct tctattttct tttgggagat 900 cacttcaggg acatgctgatgaatcaactg agacacaact tcaaatccct tacatccttt 960 agcagatggg ctcatgaactcctactttca ttcagagaaa agtga 1005 36 334 PRT Homo sapiens 36 Met Leu GlyIle Met Ala Trp Asn Ala Thr Cys Lys Asn Trp Leu Ala 1 5 10 15 Ala GluAla Ala Leu Glu Lys Tyr Tyr Leu Ser Ile Phe Tyr Gly Ile 20 25 30 Glu PheVal Val Gly Val Leu Gly Asn Thr Ile Val Val Tyr Gly Tyr 35 40 45 Ile PheSer Leu Lys Asn Trp Asn Ser Ser Asn Ile Tyr Leu Phe Asn 50 55 60 Leu SerVal Ser Asp Leu Ala Phe Leu Cys Thr Leu Pro Met Leu Ile 65 70 75 80 ArgSer Tyr Ala Asn Gly Asn Trp Ile Tyr Gly Asp Val Leu Cys Ile 85 90 95 SerAsn Arg Tyr Val Leu His Ala Asn Leu Tyr Thr Ser Ile Leu Phe 100 105 110Leu Thr Phe Ile Ser Ile Asp Arg Tyr Leu Ile Ile Lys Tyr Pro Phe 115 120125 Arg Glu His Leu Leu Gln Lys Lys Glu Phe Ala Ile Leu Ile Ser Leu 130135 140 Ala Ile Trp Val Leu Val Thr Leu Glu Leu Leu Pro Ile Leu Pro Leu145 150 155 160 Ile Asn Pro Val Ile Thr Asp Asn Gly Thr Thr Cys Asn AspPhe Ala 165 170 175 Ser Ser Gly Asp Pro Asn Tyr Asn Leu Ile Tyr Ser MetCys Leu Thr 180 185 190 Leu Leu Gly Phe Leu Ile Pro Leu Phe Val Met CysPhe Phe Tyr Tyr 195 200 205 Lys Ile Ala Leu Phe Leu Lys Gln Arg Asn ArgGln Val Ala Thr Ala 210 215 220 Leu Pro Leu Glu Lys Pro Leu Asn Leu ValIle Met Ala Val Val Ile 225 230 235 240 Phe Ser Val Leu Phe Thr Pro TyrHis Val Met Arg Asn Val Arg Ile 245 250 255 Ala Ser Arg Leu Gly Ser TrpLys Gln Tyr Gln Cys Thr Gln Val Val 260 265 270 Ile Asn Ser Phe Tyr IleVal Thr Arg Pro Leu Ala Phe Leu Asn Ser 275 280 285 Val Ile Asn Pro ValPhe Tyr Phe Leu Leu Gly Asp His Phe Arg Asp 290 295 300 Met Leu Met AsnGln Leu Arg His Asn Phe Lys Ser Leu Thr Ser Phe 305 310 315 320 Ser ArgTrp Ala His Glu Leu Leu Leu Ser Phe Arg Glu Lys 325 330 37 1296 DNA Homosapiens 37 atgcaggcgc ttaacattac cccggagcag ttctctcggc tgctgcgggaccacaacctg 60 acgcgggagc agttcatcgc tctgtaccgg ctgcgaccgc tcgtctacaccccagagctg 120 ccgggacgcg ccaagctggc cctcgtgctc accggcgtgc tcatcttcgccctggcgctc 180 tttggcaatg ctctggtgtt ctacgtggtg acccgcagca aggccatgcgcaccgtcacc 240 aacatcttta tctgctcctt ggcgctcagt gacctgctca tcaccttcttctgcattccc 300 gtcaccatgc tccagaacat ttccgacaac tggctggggg gtgctttcatttgcaagatg 360 gtgccatttg tccagtctac cgctgttgtg acagaaatgc tcactatgacctgcattgct 420 gtggaaaggc accagggact tgtgcatcct tttaaaatga agtggcaatacaccaaccga 480 agggctttca caatgctagg tgtggtctgg ctggtggcag tcatcgtaggatcacccatg 540 tggcacgtgc aacaacttga gatcaaatat gacttcctat atgaaaaggaacacatctgc 600 tgcttagaag agtggaccag ccctgtgcac cagaagatct acaccaccttcatccttgtc 660 atcctcttcc tcctgcctct tatggtgatg cttattctgt acagtaaaattggttatgaa 720 ctttggataa agaaaagagt tggggatggt tcagtgcttc gaactattcatggaaaagaa 780 atgtccaaaa tagccaggaa gaagaaacga gctgtcatta tgatggtgacagtggtggct 840 ctctttgctg tgtgctgggc accattccat gttgtccata tgatgattgaatacagtaat 900 tttgaaaagg aatatgatga tgtcacaatc aagatgattt ttgctatcgtgcaaattatt 960 ggattttcca actccatctg taatcccatt gtctatgcat ttatgaatgaaaacttcaaa 1020 aaaaatgttt tgtctgcagt ttgttattgc atagtaaata aaaccttctctccagcacaa 1080 aggcatggaa attcaggaat tacaatgatg cggaagaaag caaagttttccctcagagag 1140 aatccagtgg aggaaaccaa aggagaagca ttcagtgatg gcaacattgaagtcaaattg 1200 tgtgaacaga cagaggagaa gaaaaagctc aaacgacatc ttgctctctttaggtctgaa 1260 ctggctgaga attctccttt agacagtggg cattaa 1296 38 431 PRTHomo sapiens 38 Met Gln Ala Leu Asn Ile Thr Pro Glu Gln Phe Ser Arg LeuLeu Arg 1 5 10 15 Asp His Asn Leu Thr Arg Glu Gln Phe Ile Ala Leu TyrArg Leu Arg 20 25 30 Pro Leu Val Tyr Thr Pro Glu Leu Pro Gly Arg Ala LysLeu Ala Leu 35 40 45 Val Leu Thr Gly Val Leu Ile Phe Ala Leu Ala Leu PheGly Asn Ala 50 55 60 Leu Val Phe Tyr Val Val Thr Arg Ser Lys Ala Met ArgThr Val Thr 65 70 75 80 Asn Ile Phe Ile Cys Ser Leu Ala Leu Ser Asp LeuLeu Ile Thr Phe 85 90 95 Phe Cys Ile Pro Val Thr Met Leu Gln Asn Ile SerAsp Asn Trp Leu 100 105 110 Gly Gly Ala Phe Ile Cys Lys Met Val Pro PheVal Gln Ser Thr Ala 115 120 125 Val Val Thr Glu Met Leu Thr Met Thr CysIle Ala Val Glu Arg His 130 135 140 Gln Gly Leu Val His Pro Phe Lys MetLys Trp Gln Tyr Thr Asn Arg 145 150 155 160 Arg Ala Phe Thr Met Leu GlyVal Val Trp Leu Val Ala Val Ile Val 165 170 175 Gly Ser Pro Met Trp HisVal Gln Gln Leu Glu Ile Lys Tyr Asp Phe 180 185 190 Leu Tyr Glu Lys GluHis Ile Cys Cys Leu Glu Glu Trp Thr Ser Pro 195 200 205 Val His Gln LysIle Tyr Thr Thr Phe Ile Leu Val Ile Leu Phe Leu 210 215 220 Leu Pro LeuMet Val Met Leu Ile Leu Tyr Ser Lys Ile Gly Tyr Glu 225 230 235 240 LeuTrp Ile Lys Lys Arg Val Gly Asp Gly Ser Val Leu Arg Thr Ile 245 250 255His Gly Lys Glu Met Ser Lys Ile Ala Arg Lys Lys Lys Arg Ala Val 260 265270 Ile Met Met Val Thr Val Val Ala Leu Phe Ala Val Cys Trp Ala Pro 275280 285 Phe His Val Val His Met Met Ile Glu Tyr Ser Asn Phe Glu Lys Glu290 295 300 Tyr Asp Asp Val Thr Ile Lys Met Ile Phe Ala Ile Val Gln IleIle 305 310 315 320 Gly Phe Ser Asn Ser Ile Cys Asn Pro Ile Val Tyr AlaPhe Met Asn 325 330 335 Glu Asn Phe Lys Lys Asn Val Leu Ser Ala Val CysTyr Cys Ile Val 340 345 350 Asn Lys Thr Phe Ser Pro Ala Gln Arg His GlyAsn Ser Gly Ile Thr 355 360 365 Met Met Arg Lys Lys Ala Lys Phe Ser LeuArg Glu Asn Pro Val Glu 370 375 380 Glu Thr Lys Gly Glu Ala Phe Ser AspGly Asn Ile Glu Val Lys Leu 385 390 395 400 Cys Glu Gln Thr Glu Glu LysLys Lys Leu Lys Arg His Leu Ala Leu 405 410 415 Phe Arg Ser Glu Leu AlaGlu Asn Ser Pro Leu Asp Ser Gly His 420 425 430 39 24 DNA Homo sapiens39 ctgtgtacag cagttcgcag agtg 24 40 24 DNA Homo sapiens 40 gagtgccaggcagagcaggt agac 24 41 31 DNA Homo sapiens 41 cccgaattcc tgcttgctcccagcttggcc c 31 42 32 DNA Homo sapiens 42 tgtggatcct gctgtcaaaggtcccattcc gg 32 43 20 DNA Homo sapiens 43 tcacaatgct aggtgtggtc 20 4422 DNA Homo sapiens 44 tgcatagaca atgggattac ag 22 45 511 DNA Homosapiens 45 tcacaatgct aggtgtggtc tggctggtgg cagtcatcgt aggatcacccatgtggcacg 60 tgcaacaact tgagatcaaa tatgacttcc tatatgaaaa ggaacacatctgctgcttag 120 aagagtggac cagccctgtg caccagaaga tctacaccac cttcatccttgtcatcctct 180 tcctcctgcc tcttatggtg atgcttattc tgtacgtaaa attggttatgaactttggat 240 aaagaaaaga gttggggatg gttcagtgct tcgaactatt catggaaaagaaatgtccaa 300 aatagccagg aagaagaaac gagctgtcat tatgatggtg acagtggtggctctctttgc 360 tgtgtgctgg gcaccattcc atgttgtcca tatgatgatt gaatacagtaattttgaaaa 420 ggaatatgat gatgtcacaa tcaagatgat ttttgctatc gtgcaaattattggattttc 480 caactccatc tgtaatccca ttgtctatgc a 511 46 21 DNA Homosapiens 46 ctgcttagaa gagtggacca g 21 47 22 DNA Homo sapiens 47ctgtgcacca gaagatctac ac 22 48 21 DNA Homo sapiens 48 caaggatgaaggtggtgtag a 21 49 23 DNA Homo sapiens 49 gtgtagatct tctggtgcac agg 2350 21 DNA Homo sapiens 50 gcaatgcagg tcatagtgag c 21 51 27 DNA Homosapiens 51 tggagcatgg tgacgggaat gcagaag 27 52 27 DNA Homo sapiens 52gtgatgagca ggtcactgag cgccaag 27 53 23 DNA Homo sapiens 53 gcaatgcaggcgcttaacat tac 23 54 22 DNA Homo sapiens 54 ttgggttaca atctgaaggg ca 2255 23 DNA Homo sapiens 55 actccgtgtc cagcaggact ctg 23 56 24 DNA Homosapiens 56 tgcgtgttcc tggaccctca cgtg 24 57 29 DNA Homo sapiens 57caggccttgg attttaatgt cagggatgg 29 58 27 DNA Homo sapiens 58 ggagagtcagctctgaaaga attcagg 27 59 27 DNA Homo sapiens 59 tgatgtgatg ccagatactaatagcac 27 60 27 DNA Homo sapiens 60 cctgattcat ttaggtgaga ttgagac 27 6121 DNA Homo sapiens 61 gacaggtacc ttgccatcaa g 21 62 22 DNA Homo sapiens62 ctgcacaatg ccagtgataa gg 22 63 27 DNA Homo sapiens 63 ctgacttcttgttcctggca gcagcgg 27 64 27 DNA Homo sapiens 64 agaccagcca gggcacgctgaagagtg 27 65 32 DNA Homo sapiens 65 gatcaagctt ccatcctact gaaaccatgg tc32 66 35 DNA Homo sapiens 66 gatcagatct cagttccaat attcacacca ccgtc 3567 22 DNA Homo sapiens 67 ctggtgtgct ccatggcatc cc 22 68 22 DNA Homosapiens 68 gtaagcctcc cagaacgaga gg 22 69 24 DNA Homo sapiens 69cagcgcaggg tgaagcctga gagc 24 70 24 DNA Homo sapiens 70 ggcacctgctgtgacctgtg cagg 24 71 22 DNA Homo sapiens 71 gtcctgccac ttcgagacat gg 2272 23 DNA Homo sapiens 72 gaaacttctc tgcccttacc gtc 23 73 26 DNA Homosapiens 73 ccaacaccag catccatggc atcaag 26 74 27 DNA Homo sapiens 74ggagagtcag ctctgaaaga attcagg 27

What is claimed is:
 1. A method for identifying one or more candidatecompounds as modulators of a G protein-coupled receptor comprising anendogenous human ARE-2 polypeptide, wherein said endogenous human ARE-2polypeptide is encoded by a nucleotide sequence, said nucleotidesequence being obtainable by performing nucleic acid hybridization,under stringent conditions, on a sample of human DNA library usingspecific probe EST clone 68530, comprising the steps of: (a) contactingsaid one or more compounds with a host cell or with membrane of a hostcell that expresses said receptor; and (b) measuring the ability of thecompound or compounds to inhibit or stimulate functionality of saidreceptor.
 2. The method of claim 1 wherein said host cell comprises anexpression vector, said expression vector comprising a polynucleotideencoding a G protein-coupled receptor comprising an endogenous humanARE-2 polypeptide, wherein said endogenous human ARE-2 polypeptide isencoded by a nucleotide sequence, said nucleotide sequence beingobtainable by performing nucleic acid hybridization, under stringentconditions, on a sample of human DNA library using specific probe ESTclone
 68530. 3. A method for identifying one or more candidate compoundsas modulators of a G protein-coupled receptor consisting of anendogenous human ARE-2 polypeptide, wherein said endogenous human ARE-2polypeptide is encoded by a nucleotide sequence, said nucleotidesequence being obtainable by performing nucleic acid hybridization,under stringent conditions, on a sample of human DNA library usingspecific probe EST clone 68530, comprising the steps of: (c) contactingsaid one or more compounds with a host cell or with membrane of a hostcell that expresses said receptor; and (d) measuring the ability of thecompound or compounds to inhibit or stimulate functionality of saidreceptor.
 4. The method of claim 3 wherein said host cell comprises anexpression vector, said expression vector comprising a polynucleotideencoding a G protein-coupled receptor consisting of an endogenous humanARE-2 polypeptide, wherein said endogenous human ARE-2 polypeptide isencoded by a nucleotide sequence, said nucleotide sequence beingobtainable by performing nucleic acid hybridization, under stringentconditions, on a sample of human DNA library using specific probe ESTclone
 68530. 5. A method for identifying one or more candidate compoundsas modulators of a G protein-coupled receptor comprising the polypeptideof SEQ ID NO:20, comprising the steps of: (a) contacting said one ormore compounds with a host cell or with membrane of a host cell thatexpresses said receptor; and (b) measuring the ability of the compoundor compounds to inhibit or stimulate functionality of said receptor. 6.The method of claim 5 wherein said host cell comprises an expressionvector, said expression vector comprising a polynucleotide encoding a Gprotein-coupled receptor, said receptor comprising the polypeptide ofSEQ ID NO:20.
 7. A method for identifying one or more candidatecompounds as modulators of a G protein-coupled receptor consisting ofthe polypeptide of SEQ.ID.NO.:20, comprising the steps of: (a)contacting said one or more compounds with a host cell or with membraneof a host cell that expresses said receptor; and (b) measuring theability of the compound or compounds to inhibit or stimulatefunctionality of said receptor.
 8. The method of claim 7 wherein saidhost cell comprises an expression vector, said expression vectorcomprising a polynucelotide encoding a G protein-coupled receptor, saidreceptor consisting of the polypeptide of SEQ.ID.NO.:20.
 9. A method foridentifying one or more candidate compounds as modulators of a Gprotein-coupled receptor comprising an endogenous human ARE-2polypeptide, wherein said endogenous human ARE-2 polypeptide is encodedby a nucleotide sequence, said nucleotide sequence being obtainable byperforming nucleic acid hybridization, under stringent conditions, on asample of human DNA library using specific probe EST clone 68530, andwherein the amino acid at amino acid position 285 of said endogenoushuman ARE-2 polypeptide is substituted with another amino acid,comprising the steps of: (a) contacting said one or more compounds witha host cell or with membrane of a host cell that expresses saidreceptor; and (b) measuring the ability of the compound or compounds toinhibit or stimulate functionality of said receptor.
 10. The method ofclaim 9 wherein said host cell comprises an expression vector, saidexpression vector comprising a polynucleotide encoding a Gprotein-coupled receptor comprising an endogenous human ARE-2polypeptide, wherein said endogenous human ARE-2 polypeptide is encodedby a nucleotide sequence, said nucleotide sequence being obtainable byperforming nucleic acid hybridization, under stringent conditions, on asample of human DNA library using specific probe EST clone 68530, andwherein the amino acid at amino acid position 285 of said endogenoushuman ARE-2 polypeptide is substituted with another amino acid.
 11. Amethod for identifying one or more candidate compounds as modulators ofa G protein-coupled receptor consisting of an endogenous human ARE-2polypeptide, wherein said endogenous human ARE-2 polypeptide is encodedby a nucleotide sequence, said nucleotide sequence being obtainable byperforming nucleic acid hybridization, under stringent conditions, on asample of human DNA library using specific probe EST clone 68530, andwherein the amino acid at amino acid position 285 of said endogenoushuman ARE-2 polypeptide is substituted with another amino acid,comprising the steps of: (a) contacting said one or more compounds witha host cell or with membrane of a host cell that expresses saidreceptor; and (b) measuring the ability of the compound or compounds toinhibit or stimulate functionality of said receptor.
 12. The method ofclaim 11 wherein said host cell comprises an expression vector, saidexpression vector comprising a polynucleotide encoding a Gprotein-coupled receptor consisting of an endogenous human ARE-2polypeptide, wherein said endogenous human ARE-2 polypeptide is encodedby a nucleotide sequence, said nucleotide sequence being obtainable byperforming nucleic acid hybridization, under stringent conditions, on asample of human DNA library using specific probe EST clone 68530, andwherein the amino acid at amino acid position 285 of said endogenoushuman ARE-2 polypeptide is substituted with another amino acid.
 13. Amethod of claim 9 wherein the amino acid at amino acid position 285 ofsaid endogenous human ARE-2 polypeptide is glycine and wherein theglycine at said amino acid position 285 is substituted with an aminoacid other than glycine.
 14. The method of claim 13 wherein said aminoacid other than glycine is lysine.
 15. The method of claim 13 whereinsaid host cell comprises an expression vector, said expression vectorcomprising a polynucleotide encoding a G protein-coupled receptorcomprising an endogenous human ARE-2 polypeptide, wherein saidendogenous human ARE-2 polypeptide is encoded by a nucleotide sequence,said nucleotide sequence being obtainable by performing nucleic acidhybridization, under stringent conditions, on a sample of human DNAlibrary using specific probe EST clone 68530, wherein the amino acid atamino acid position 285 of said endogenous human ARE-2 polypeptide isglycine and wherein the glycine at said amino acid position 285 issubstituted with an amino acid other than glycine.
 16. The method ofclaim 15 wherein said amino acid other than glycine is lysine.
 17. Amethod of claim 11 wherein the amino acid at amino acid position 285 ofsaid endogenous human ARE-2 polypeptide is glycine and wherein theglycine at said amino acid position 285 is substituted with an aminoacid other than glycine.
 18. The method of claim 17 wherein said aminoacid other than glycine is lysine.
 19. The method of claim 17 whereinsaid host cell comprises an expression vector, said expression vectorcomprising a polynucleotide encoding a G protein-coupled receptorconsisting of an endogenous human ARE-2 polypeptide, wherein saidendogenous human ARE-2 polypeptide is encoded by a nucleotide sequence,said nucleotide sequence being obtainable by performing nucleic acidhybridization, under stringent conditions, on a sample of human DNAlibrary using specific probe EST clone 68530, wherein the amino acid atamino acid position 285 of said endogenous human ARE-2 polypeptide isglycine and wherein the glycine at said amino acid position 285 issubstituted with an amino acid other than glycine.
 20. The method ofclaim 19 wherein said amino acid other than glycine is lysine.
 21. Amethod for identifying one or more candidate compounds as modulators ofa G protein-coupled receptor comprising the polypeptide of SEQ ID NO:20,wherein the glycine at amino acid position 285 of SEQ ID NO:20 issubstituted with an amino acid other than glycine, comprising the stepsof: (a) contacting said one or more compounds with a host cell or withmembrane of a host cell that expresses said receptor; and (b) measuringthe ability of the compound or compounds to inhibit or stimulatefunctionality of said receptor.
 22. The method of claim 21 wherein theglycine at amino acid position 285 is substituted with lysine.
 23. Themethod of claim 21 wherein said host cell comprises an expressionvector, said expression vector comprising a polynucleotide encoding a Gprotein-coupled receptor comprising the polypeptide of SEQ ID NO:20,wherein the glycine at amino acid position 285 of SEQ ID NO:20 issubstituted with an amino acid other than glycine.
 24. A method foridentifying one or more candidate compounds as modulators of a Gprotein-coupled receptor consisting of the polypeptide of SEQ ID NO:20,wherein the glycine at amino acid position 285 of SEQ ID NO:20 issubstituted with an amino acid other than glycine, comprising the stepsof: (a) contacting said one or more compounds with a host cell or withmembrane of a host cell that expresses said receptor; and (b) measuringthe ability of the compound or compounds to inhibit or stimulatefunctionality of said receptor.
 25. The method of claim 24 wherein theglycine at amino acid position 285 is substituted with lysine.
 26. Themethod of claim 24 wherein said host cell comprises an expressionvector, said expression vector comprising a polynucleotide encoding a Gprotein-coupled receptor consisting of the polypeptide of SEQ ID NO:20,wherein the glycine at amino acid position 285 of SEQ ID NO:20 issubstituted with an amino acid other than glycine.
 27. A method ofmodulating the functionality of a G protein-coupled receptor comprisingan endogenous human ARE-2 polypeptide, wherein said endogenous humanARE-2 polypeptide is encoded by a nucleotide sequence, said nucleotidesequence being obtainable by performing nucleic acid hybridization on asample of human genomic DNA using specific probe EST clone 68530,comprising the step of contacting the receptor with a modulator of thereceptor.